65 2
.
CARBAMATES (URETHANES) SEMICARBAZIDES. UREAS
.
"Murray a n d Ronzio. J . Am Chem. Soc., 71. 2245 (1947)
@ L a m c h e n . J Chem. Soc., 748 (1750) .
41 Kurzer. Org S y n t h e s e s . 31. 8 (1951) including n o t e 5 .
4'Kurzer. Org S y n t h e s e s . 31. 11 (1951) including n o t e 5
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C h 23
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Amines
CONTENTS
METHOD
.
.
.
425 Reduction of Nitro Compounds ................................................................
426 Reduction of O x i m e s ..................................................................................
427 Reduction of N i t r i l e s ................................................................................
428 Reduction of Amides ..................................................................................
427 . Reduction of Schiff B a s e s ........................................................................
430 Reduction of Aromatic Amines ................................................................
431 R e d u c t i v e Alkylation (or R e d u c t i v e Amination) ....................................
432 R e d u c t i v e Alkylation o f Amines ( L e u c k a r t ) ..........................................
433 R e d u c t i v e C l e a v a g e o f Azo Compounds ..................................................
434 C a t a l y t i c Debenzylation of N - B e n z y l d i a l k y l a m ~ n e s..............................
43 5 Ammonoly s i s of Halogen Compounds ......................................................
436 Alkylation o f Amines ................................................................................
437 Interaction of Hexarnine a n d Halogen Compounds ................................
438 R e p l a c e m e n t of Hydroxyl Groups by Amino Groups ..............................
437 Amination of Aromatic Nuclei ..................................................................
440 Rearrangement o f N-Alkylanilines ..........................................................
441 Amination o f C y c l i c I m i n e s ......................................................................
442 Amination of O x i d e s ..................................................................................
443 Amination of Unsaturated Compounds ....................................................
444 . Aminome thy lation (Mannich) ....................................................................
445 Aminomethylation of Alcohols ..................................................................
446 Degradation of Amides (Hofmann) ............................................................
447 Degradation o f Acyl Azides (Curtius) ....................................................
448 Degradation o f Hydroxamic A c i d s ( L d s s e n ) ..........................................
447 Interaction of Hydrazoic Acid and Carbonyl Compounds (Schmidt) ....
450 Hydrolysis of I s o c y a n a t e s , I s o t h i o c y a n a t e s , Urethanes, and U r e a s ..
451 H y d r o l y s i s o f N-Substituted Amides ........................................................
452 H y d r o l y s i s of N S u b s t i t u t e d P h t h a l i m i d e s (Gabriel) ............................
453 H y d r o l y s i s o f Nitrosoanilines ..................................................................
454 H y d r o l y s i s o f Quaternary Imine S a l t s ......................................................
455 H y d r o l y s i s of C y a n a m i d e s ........................................................................
456 Ring Dehydrogenation ................................................................................
457 C o n d e n s a t i o n of Grignard R e a g e n t s and 0-Methylhydroxylamine ........
458, Addition of Grignard R e a g e n t s to Schiff B a s e s ....................................
459 Interaction of Grignard R e a g e n t s and H a l o Amines ..............................
460 Reduction of Unsaturated Amines ............................................................
461 Interaction of Sodium Amide a n d Halogen Compounds ..........................
462 Rearrangement of Hydrazobenzenes ........................................................
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PAGE
Ch. 2 4
CONTENTS (continued)
METHOD
463. Interaction of Amines and P-Keto Esters .............................................
464. Condensation of Unsaturated Amines and Aromatic Compounds ........
Table 81. Amines ................................................................................................
Table 82. Diamines ............................................................................................
Table 83. Olefinic Amines ................................................................................
Table 84. Acetylenic Amines ............................................................................
Table 85. Halo Amines ......................................................................................
Table 86. Hydroxy Amines ................................................................................
Table 87. Amino Ethets ....................................................................................
Table 88. Amino Aldehydes ..............................................................................
Table 89. Amino Ketones ..................................................................................
Table 9 0 . Amino A c i d s ......................................................................................
Table 91. Amino Esters ....................................................................................
Table 92. Amino Cyanides ................................................................................
References ..........................................................................................................
PAGE
682
682
683
691
694
695
695
698
70 2
704
705
706
710
711
71 5
425. Reduction of Nitro Compounds
T h i s method h a s had limited application for making a l i p h a t i c a m i n e s 2
although it a s s u m e s increasing importance in view of t h e commercial
availability of the nitroparaffins a n d t h e development of p r o c e s s e s for
their ready conversion t o nitro olefins;" 4'77' 'l' nitro alcohols,' nitro
ethers,'" nitro a m i n e ~ , ~and
' ~ nitro cyanides,'19 a l l of which have been
reduced to the corresponding amino compounds.
Aromatic primary amines a r e commonly prepared from nitro compounds
by t h e a c t i o n of one of s e v e r a l reducing a g e n t s ; t h e reaction h a s been
d i ~ c u s s e d . ' ~ ' Reduction with a metal-acid combination like granulated
iron and a s m a l l quantity of a c i d g i v e s e x c e l l e n t r e s u l t s . B y t h i s procedure, many aromatic amines have b e e n prepared, including aniline (86%),
0-toluidine (73%), 4-aminobiphenyl (93%), a n d a-naphthylamine (96%).'**
Another common combination is tin a n d hydrochloric acid, but reduction
may be accompanied by nuclear halogenation, particularly in t h e treatment of 0-substituted nitrobenzenes. T h e a c t i o n of z i n c d u s t and aqueous
alcohol in the p r e s e n c e of calcium chloride, e s s e n t i a l l y neutral condit i o n s , is s u f f i c i e n t t o convert 2-nitrofluorene t o 2-aminofluorene (82%).11
Aluminum amalgam and aqueous alcohol, s t i l l another neutral combination, h a s been s u c c e s s f u l l y applied in the formation of 3-aminoacenaphthene (85%)" and the isomeric aminoacridines (70-75%):'
Lithium aluminum hydride is a n effective reductant for certain nitroiilefins in the thiophene s e r i e s .3'p
METHOD 425
655
C a t a l y t i c hydrogenation is performed in alcohol solution over Raney
nickel a t 25" t o 100" a n d 3 0 atm.14 or over platinum oxide a t room temperature and 1 t o 2 am.'* T h e reaction is highly exothermic; therefore,
precautions s h o u l d b e taken a g a i n s t e x c e s s i v e reaction temperatures.
T y p i c a l illustrations a r e found in the preparations of 2-amino*-cymene
(90%)'' a n d 3,4-diethylaniline (90%);' Heterocyclic nitro compounds in
t h e quinoline2' and diDenzothiophene3' s e r i e s a l s o respond favorably t o
c a t a l y t i c hydrogenation.
In addition t o t h e s e procedures, electrolytic reduction of t h e nitro
group h a s b e e n accomplished, a s illustrated by t h e preparation of o-aminocyclohexy lbenzene (85%); however, t h e procedure is rarely employed. An
apparatus for large-scale runs h a s been d e s c r i b e d t 7 and a comprehensive
review of electrolytic r e a c t i o n s h a s been given?0'
Often under t h e non-acidic conditions, t h e reduction s t o p s a t the hyT h u s phenylhydroxylamine, C,H,NHOH, is s yndroxylamine s t a g e .l6'
thesized in 68% yield by the a c t i o n of z i n c d u s t a n d water on
nitrobenzene
Certain aliphatic diamines have b e e n prepared by reduction of nitro
amines with
or aluminum amalgam.39 T h e starting materials
a r e readily obtained by t h e reaction of nitroparaffins with formaldehyde
and amines (method 444).
Aromatic diamines and other polyfunctional aromatic amino compounds
a r e prepared by the above general procedures. In the hydrogenation of
polynitro compounds in t h e presence of R a n e y nickel c a t a l y s t , e t h y l
a c e t a t e h a s b e e n found t o be a better s o l v e n t than aliphatic alcohols."
T h e s y n t h e s i s of 2,4-diaminotoluene is accomplished by reduction of the
corresponding dinitro compound with iron filings and hydrochloric a c i d
(8%):'
Alkaline reducing a g e n t s , including ammonium sulfide, sodium
s u l f i d e , z i n c and alcoholic a l k a l i , etc., have a l s o b e e n employed. F o r
example, o - p h e n ~ l e n e d i a m i n eis s y n t h e s i z e d in 85% t o 9m yield by reducing o-nitroaniline with z i n c and alcoholic alkali."
Certain unsaturated amino compounds like t h e cis- and trans-p,p'diaminostilbene? and p,p'-diaminotolane a r e prepared by s e l e c t i v e hydrogenation of the corresponding dinitro compounds u s ing R a n e y nickel
47 T h e reduction h a s a l s o b e e n accomplished with
c a t a l y s t (60-89?4)."'
hydrazine hydrate in t h e presence of alkali.'6
Haloanilines a r e obtained from halonitrobenzenes preferably b y the
iron-acid reduction procedure>' 'l Nuclear halogenation o c c u r s during
the reduction of nitrobenzene by s t a n n o u s chloride in t h e presence of
a c e t i c anhydride; a quantitative yield of p-chloroacetanilide is ~btained.'~
Hydrogenation of halonitrobenzenes over R a n e y nickel c a t a l y s t is ~ O S s i b l e provided t h a t the temperature is kept below 150°, a t which point
65 6
AMINES
Ch. 24
dehalogenation occur^.^"*^^ T h e iodine atom i s the most susceptible of
the halogens to replacement during catalytic hydrogenation of the nitro
group; however reduction by stannous chloride and hydrochloric acid has
been successful, e.g., m-iodoaniline (83%).53
Aliphatic nitro alcohols, conveniently derived by the condensation of
nitroparaffins with aldehyde^,'^ are reduced to amino alcohols in almost
quantitative yields by the action of iron powder and mineral acid.' Rest
results are obtained when an e x c e s s of acid i s present. The procedure
i s illustrated by the synthesis of 2-amino-l-butanol (90%);
T h i s same reducing agent h a s been successfully employed in the synthesis of 2-amino-l-phenyl-lpropanol (70%)." T h e formation of amino
alcohols by catalytic hydrogenation over Raney nickel catalyst has been
accomplished. However, because of the instability of the nitro alcohols
in basic media, lower amines are a l s o formed.
RCHO
METHOD 425
657
the presence of formaldehyde (27%)530(cf. method 431). Reduction of the
niuoacetophenones has been accomplished by metal-acid combinations
and by selective hydrogenations over Raney nickel and platinum oxide
catalysts; a comparison of t h e s e procedures has been made in the preparation of o- and m-aminoacetophenones.69*70 Other methods of preparation
for o a m i n o ketones have been summarized."
p-Aminophenylacetic a c i d
i s best obtained by reduction of the nitro compound with ammonium sulAmino e s t e r s are readily obtained by catalytic reduction of
fide
nitro e s t e r s over platinum oxide, e.g., ethyl p-aminobenzoate (lOO%)." A
novel synthesis of ethyl m-aminophenylacetate from m-nitrobenzaldehyde
consists in converting t h i s substance to m-nitro-0-benzoylmandelonitrile
by the action of benzoyl chloride and sodium cyanide, followed by alcoholysis and hydrogenation with simultaneous hydrogenolysis (67%
over-all)."
+ C,BSNH, + H, 5 KCH,NHC2HS
T h e s e by-products are suppressed by hydrogenating in a n acid mediun;,
e.g., in the presence of carbonic, acetic, or oxalic
The acid-sensitive amino phenols can be obtained by the reduction of
n i u o phenols with sodium sulfide or sodium hydrogen sulfite5' or by treatment of the p-tolylsulfonic e s t e r s with iron and a c e t i c acid.59 Also, hydrogenation over Raney nickel a t 100° gives excellent results.14
Aromatic nitro alcohols are converted by hydrogenation6" or by the
action of metals and acids. Various combinations have bcen compared in
the preparation of ~-(4-amin0~hen~l)-ethanol.~~
Other functional groups may be present during reduction. Aromatic
amino ethers are prepared by the same general procedures described above,
e.g., m-aminoanisole
and 2aminodiphenyl ether (94%).6s The
reduction of o-nitrobenzaldehyde t o the sensitive o-aminobenzaldehyde i s
successfully accomplished by the action of ferrous sulfate and ammonia
(75%).67 m-Dimethylaminobenzaldehyde i s formed by reduction of the
nitro a c e t a l in aqueous solution with sodium sulfide followed by methylation (74% over-all)68 or by catalytic reduction of m-nitrobenzaldehyde in
3-Aminobenzonitrile i s prepared by reduction of 3-nitrobenzoniuile by
sodium disulfide in aqueous suspension (63%). T h i s reagent causes some
hydrolysis of the cyano
A selective hydrogenation of the more
reactive nitro group in the presence of the cyano group can a l s o be done,
e.g., in the preparation of p-aminobenzyl cyanide (73%).7'
Partial reduction of aromatic polynitro compounds leads t o nitro amines.
The most successful reagents are the alkali metal or ammonium sulfides
in aqueous alcohol."' In some instances, sodium bicarbonate combined
with sodium sulfide gives better results because of the formation of
sodium hydrosulfide, which i s believed t o b e the main reducing agent.
Nitro comAlso, aqueous methanol is preferred t o aqueous ethanol."
pounds that are sparingly soluble in alcohol solutions may be reduced by
hydrogen sulfide in pyridine solution."
Very often reduction of an aromatic nitro compound i s carried out in the
presence of acetic anhydride, whereby the corresponding acetamido compound i s formed .49 Amino amides are prepared by catalytic hydrogenation
of nitro amides, e.g., 2-aminoacetanilide
AMINES
Ch. 24
426. Reduction of Oximes
R,C =NOH (H? R,CHNH,
Reduction of oximes to primary amines proceeds readily and can be
accomplished with hydrogen and Raney nickel catalyst with or without
3466349
Primary amines formed from
high pressures (50-90%).174' '06*
aldoximes are accompanied by secondary amines, (RCH,),NH. The reduction may a l s o be carried out with sodium and absolute ethanol, a s illustrated by the synthesis of n-heptylamine (73%)?50 The action of zinc
d u s t and acetic acid is effective in the formation of Pfluorylamine
(74%)?51 Lithium aluminum hydride i s a good reagent, a s shown by the
reduction of 2,2-diphenylcyclohexanone oxime t o 2,2-diphenylcyclohexylamine (80%).545
Aliphatic diamines are made by reduction of amino oximes by these
same general procedure^.'^^"^^ Sometimes catalytic hydrogenation gives
low-boiling cleavage products ?l9
T h e reduction of isonitroso ketones with hydrogen and platinum in the
presence of hydrochloric acid gives amino ketones or amino alcohols,
e.g., l-phenyl-2-amino-l-propanol (98%)356and a-aminopropiophenone
(88%
T h e reduction of a-oximino acids to a-amino a c i d s i s accomplished by
catalytic hydrogenation with a Raney nickel361 or palladium-charcoal36" 363
catalyst or by the action of sodium or aluminum amalgam."41 364-367
Several procedures involving the formation of a-oximino acid intermediates for the synthesis of a-amino acids have been d e s ~ r i b e d ' ~ ~ " ~ ~
(cf. method 385). One outstanding synthesis c o n s i s t s in the production
of a-oximino acids or e s t e r s by the action of a nitrite on a substituted
acetoacetic or malonic ester?60*
Oximes carrying a second group like a hydroxyl, carbonyl, or carbalkoxyl may form cyclic products, such a s pyrazines from a-keto oximes
and pyrrolidones from y-oximino esters, upon r e d ~ c t i o n ? ~ '
RCN + H,
NH
+ RCH,NH,
Catalytic hydrogenation of aliphatic and aromatic n i u i l e s yields primary and secondary amines ."5* '09 Formation of the secondary products
c a n be suppressed (1) by carrying out the reduction in acetic anhydride,
which acetylates the primary amine ancl prevents its reaction with the
intermediate aldimine (platinum catalyst);307(2) by reducing in the prese n c e of ammonia (nickel catalyst);'03*310 or (3) by simply hydrogenating
a s rapidly a s possible with a relatively large amount of ~ a t a l y s t . ' ~
Temperatures above 150' during hydrogenation favor the formation of the
secondary amine by the elimination of ammonia from the primary amine,
viz., ZRNH, --+ R,NH + NH3?15 A typical procedure employing highpressure equipment and ammonia is illustrated by the s y n t h e s ~ sof
P-phenylethylamine ( 8 7 % ) F 0 If hydrogenation of the nitrile i s performed
in the presence of a n amine like methylamine or dimethylamine, then the
corresponding N-mono- or N,N-di-alkylamine i s formed.34' A Raney nickel
catalyst that i s useful for hydrogenation a t room temperature and low
pressure has been described?08
Reduction may a l s o be brought about by sodium and alcohol, although
extensive cleavage, of the cyanide group may occur, viz., RCN -+ RH
+ NaCN.303-306 Lithium aluminum hydride has been successfully employed for the reduction of aliphatic and aromatic nit rile^'^"^^^ a s well
a s several cyanides in the thiophene s e r i e s .,l4' 544
A large number of aliphatic diamines have been made by the reduction
of amino nitriles. Dialkylaminoacetonitriles, R,NCH,CN, are reduced
with hydrogen in the presence of ammonia (Raney nickel catalyst)316'
Unsubstituted a-amino
or with sodium and alcohol (40-8%)?04p
nitriles lose hydrogen cyanide on attempted hydrogenation and poison the
catalyst; consequently, the stable acetyl derivatives are reduced in
acetic anhydride t o give the diacetyl diamine."'
Also, the acetamido
nitriles may be converted t o 1,2-diamines through the dihydroimidazoles
with subsequent hydrolysis, a s illustrated by the preparation of 2-methyl1,2-diaminobutane (53% over-all)."'
""F
-cN
-A RR'C
H
-C T N H
NHCOCH,
RR'F
-CH,NH,
NH,
CH3
427. Reduction of Nitriles
RC)+
659
METHOD 427
H
2 RCH =NH 3
RCH,NH,
--+
RCH(NH,)NHCH,R
5 (RCH,),NH + NH,
T h e addition of primary or secondary amines to acrylonitriles, followed by catalytic reduction of the P-amino cyanides, constitutes a good
synthesis of y-aminopropylamines. T h e yields in the first s t e p are
usually in the range of 60% to 95% and in the second about 50% to
7577.195.319, 310
AMINES
RNH,
+ H,C =CHCN 4 RNHCH,CH,CN
Ha 8 NHS
Ch. 24
RNH(CH,),NH,
NI
In a similar manner, higher amino nltriles a r e reduced."'
Amines containing other functional groups have been prepared. Amino
ethers are readily made by catalytic hydrogenation or sodium-alcohol
P - H ~ ~amines
~OX
may~be
reduction of the corresponding
prepared by reduction of a-hydroxy or a-keto nitriles. Best results are.
obtained when the reduction is carried out with hydrogen and platinum or
palladium catalyst in the presence of mineral acid. In t h i s manner, substituted mandelonitriles, ArCHOHCN,112 and aroyl cyanides, ArCOCN,3"
yield P-hydroxy-&arylethylamines (24-94%). Reduction of P-keto
nitriles gives keto amines or amino alcohols; however, the yields are
poor?34 Amino acids and amino e s t e r s are similarly prepared in good
yields ."6-540
Cyanides bearing a second group in a suitable position may undergo
ring closure on hydrogenation, as illustrated by the formation of piperidine
from trimethylene cyanide and pyrrolidines from P-cyapo e s t e r s 34' (cf.
method 574).
428. Reduction of Amides
RCONH,
(2
RCH2NH,
Catalytic hydrogenation of amides t o amines requires drastic conditions: in general, a temperature of 250° t o 265O and a pressure of 200 t o
300 atm. over copper-chromium oxide catalyst using dioxane a s the
~ o l v e n t . ' ~T h e yields of primary amines from unsubstituted amides are
lowered mainly by the formation of secondary amines, viz.,
ZRNH, -+ R,NH + NH,. N-Mono- and di-substituted amides yield secondary and tertiary amines, respectively; however, considerable cleavage of
the carbon-nitrogen bonds occurs .'43
Amides are more conveniently reduced with lithium aluminum hydride
in ether solution t o yield amines with the same carbon content, e.g., triethylamine from N,N-diethylacetamide (50%) and ethyl-n-propylamine from
N-eth ylpropionamide (53%).'301 344s 'I9 T h e same conversion h a s been accomplished by an electrolytic r e d u ~ t i o n ? ~34'
"
429. Reduction of Schiff B a s e s
H1
RCH= NR' ---+ RCH,NHR'
Catalyst
METHODS 429-430
66 1
Unsymmeaical secondary amines are readily prepared in good yields by
the catalytic reduction of Schiff b a s e s a t moderate temperatures in highor low-pressure equipment. Many examples have been cited.202 The intermediate imines are prepared from primary amines and aldehydes-very
seldom from ketones-and may be used without isolation (cf. method 431).
F o r the preparation of aliphatic amines, e.g., ethyl-n-propylamine and
n-butylisoamylamine, a prereduced platinum oxide catalyst i s preferred
with alcohol a s the solvent.368s
Schiff b a s e s from the condensation of
"'or a l i p h a t i ~ ' ~37'' ~ amines
aromatic aldehydes with either aromatic
are more readily prepared and are reduced over a nickel catalyst. In this
manner, a large number of Nalkylbenzylamines having halo,13' h y d r ~ x ~ l , ~ ~ '
or
groups on the nucleus have been made. Reductions by
means of sodium and alcohol370and lithium aluminum hydride '02' 559 have
a l s o been described.
430. Reduction of Aromatic Amines
Certain amines are readily prepared by the reduction of aromatic, aryl
aliphatic, and heterocyclic amines. For example, aniline is reduced t o
cyclohexylamine by high-pressure hydrogenation in the presence of Raney
nickel catalyst or a cobalt oxide-calcium oxide catalyst. T h e reaction
occurs a t a temperature above 200°, where condensation of the primary
amine a l s o t a k e s place, viz., 2C6H11NH, 4 (C6Hl1),NH + NH,. If this
s i d e reaction is repressed by the presence of dicyclohexylamine a t the
start of the reaction, a 94% yield of cyclohexylamine i s obtained.)77
Hydrogenation of aryl aliphatic amines proceeds more readily, occurring
a t moderate temperatures and pressures over platinum catalyst in glacial
acetic acid.378s
Other reductions using this catalyst are b e s t performed
on the amines in the form of their hydro chloride^.^^^
The reduction of N-alkyl-p-nitroanilines t o the corresponding cyclohexanediamines has been carried out with hydrogen
over cobalt-on-alumina
.
and ruthenium catalysts.198 Sometimes a nuclear-substituted aniline i s
acetylated before reduction in order to avoid s i d e reactions. Thus, catalytic hydrogenation of p-acetaminophenol "'and ethyl p-acetaminophenylacetate
has been successfully accomplished with platinum catalyst a t
50-60° in the presence of acetic acid.
Other conditions for the reduction of the aromatic nucleus are discussed in method 4. The hydrogenation of heterocyclic nuclei i s treated
in method 554.
AMINES
431. Reductive Alkylation (or Reductive Amination)
RcOR'
+ NH, + H,
2 RR'cENH, + H,O
663
METHODS 431-432
Ch. 24
aldehydes (above C,) and simple ketones 'l5 respond best, usually over a
platinum catalyst.
(R'= H or alkyl)
Alkyl groups may be introduced into ammonia, a primary amine, or a
secondary amine by means of an aldehyde or ketone in the presence of a
reducing agent, such a s molecular hydrogen and a catalyst, active metals
and acids, or formic acid or one of its derivatives. When the reducing
agent is formic acid or a derivative, the reaction is known a s the Leuckart
reaction and i s discussed elsewhere (method 432). An excellent review
of the preparation of amines by reductive alkylation h a s been presented.
T h i s article includes a discussion of the scope and utility of the reaction,
a selection of experimental conditions, illustrative preparations, and a
tabulation of primary, secondary, and tertiary amines prepared thereby.'Oa
Reductive alkylation of ammonia has been proved a n effective and
highly versatile method for obtaining primary amines. The most satisfactory conditions have been catalytic hydrogenation (Raney nickel) of
the carbonyl compound in an ethanolic solution of ammonia under pressure ranging from 20 t o 150 atm. and a t temperatures in the range of 40°
t o 150°.a03-a06 Typical amines prepared in this manner include benzylamine (83%)'04 and 2-aminoheptane (8%).'06 With liquid ammonia and no
solvent, a higher pressure (330 atm.) a t the higher temperature (150°) i s
required, a s illustrated by the synthesis of a-phenylethylamine from
acetophenone (52%).'08 More recently, improved procedures for hydrogenation a t lower pressures over platinum oxide or Raney nickel have
been described.a051
Treatment of benzalacetone and furfuralacetone
under t h e s e conditions leads t o saturation of the a,P-olefinic linkage a s
well a s t o reductive alkylation?Os In general, the method is particularly
successful for obtaining aliphatic amines having five or more carbon
atoms. In a l l these reactions for making a primary amine, ammonia i s
present in e x c e s s t o minimize the formation of a secondary amine.
Secondary amines are prepared by several procedures of reductive
alkylation. A procedure similar t o that described for primary amines
may be employed; the ratio of reactants must b e changed t o a t least two
moles of the carbonyl compound t o one of ammonia. The procedure leads
t o symmetrical secondary amines and i s most s u c c e s s f u l starting with
aromatic aldehydes, a s in the formation of dibenzylamine (67%)?04
Aromatic amines like aniline, a- and P-naphthylamines, etc., a r e readily
converted t o the Nalkylamines by using aldehydes in the presence of
Raney nickel, hydrogen, and sodium acetate (24-8~%)."~'"~ Since many
aromatic amines are prepared under similar conditions by the reduction of
n i u o compounds, it is possible t o combine both reductions in a single ,
operation and convert nitro compounds t o secondary amines (31-36%).211
Tertiary amines are formed if the reduction of the nitro compound and
aldehyde i s carried out with hydrogen and platinum in the presence of
acetic acid. Nitroparaffins a s well a s aromatic nitro compounds react
(34-92%)."'
Reductive dimethylation of amines of the type
ArCH(CH,)CH,NH, and ArCH,CH(CH,)NH, with formaldehyde and hydrogen
over Raney nickel catalyst occurs in 48-97% yields?14 N-Monoalkylated
anilines are methylated in good yields by the action of formaldehyde in
the presence of zinc and mineral a c i d F 7 Many tertiary aliphatic amines
have been prepared by reductive alkylation of secondary amines with
aldehydes and ketones, the aldehydes giving better results.a16
Difunctional compounds are formed by these procedures. Diamines are
prepared by reductive amination of amino ketones
or by reductive
alkylation of diamines ?l9 A few aromatic halo amines "l and amino
ethers213 have been made. Hydroxy amines are conveniently formed by
the reductive alkylation of amino alcohols160~a2a-aa7
a s illusuated by the
synthesis of 2-isopropylaminoethanol (95%)?', N-Alkyl derivatives of
S-amino-l-pentanol are readily obtained by the reductive amination of
5-hydroxypentanal?18'230
Several a-diketones have been treated under
these conditions giving amino ketones or amino alcohols, only one carbony1 group undergoing reductive amination and the other being unaffected or reduced t o a hydroxyl group.a31 Aliphatic and aromatic amino
a c i d s c a n be converted t o their N,N-dimethyl derivatives in excellent
yields with formaldehyde and hydrogen over palladium-charcoal catalyst?3a
Aromatic nitro acids may be reduced and methylated in one operation.
Reductive amination of a-keto a c i d s yields a-amino acids?33 Sometimes
a considerable quantity of the corresponding hydroxy acid is a l s o formed;
p- and y-keto acids give little or no amino acids?33
432. Reductive Alkylation of Amines (Leuckart)
Symmetrical and unsymmetrical secondary amines are made by substituting
a primary amine for the ammonia. In t h i s reduction, the higher aliphatic
R,CO
R,CHNHCHO
Heat
3R,CHNH,
664
AMINES
Ch. 24
Reductive amination of carbonyl compounds with ammonia or amines in
the presence of a reducing agent has been discussed (method 431). When
the reducing agent i s formic acid or a derivative, the products are the
formyl derivatives of primary or secondary amines or the formates of
tertiary amines. T h e s e intermediates readily furnish the amines. A
critical discussion of the reaction along with experimental conditions and
procedures and a tabular survey of compounds has been presented.'"
Many water-insoluble ketones, aliphatic, aryl aliphatic, and heterocyclic, respond favorably t o treatment with ammonium formate or formamide
tp form with subsequent hydrolysis the primary amines. A typical procedure for the synthesis of a-phenylethylamine (66%) from acetophenone
and ammonium formate has been applied t o many other ketones (65-M%).'Nuclear alkoxyl, halo, and nitro groups are not disturbed.399*40' The reaction with formamide a s the reducing agent is catalyzed by ammonium
formate, ammonium sulfate, or magnesium chloride.'05
If the ammonium formate is substituted by N-alkylformamide, then the
formyl derivative of a secondary amine is formed.
In a similar manner, treatment with a n N,N-dialkylformamide leads to
tertiary amines; moreover, magnesium chloride, or better s t i l l calcium
chloride, catalyzes the reaction.'"
Other factors have been studied.'03
The method i s employed extensively for the methylation of primary and
secondary t o the corresponding tertiary amines by the action of formaldehyde and formic acid.
METHODS 433-435
433. Reductive Cleavage of Azo Compounds
The introduction of amino groups into phenols and ethers c a n be accomplished by the formation and reductive cleavage of their a z o compounds. The diazotizing agent may be prepared from sulfanilic acid, and
the reduction c a n be performed with sodium hydrosulfite. Excellent examples are found in the synthesis of l-amino-2-naphthol' (85%) and 4amino-l-naphthol (75%).554
434. Catalytic Debenzylation of N-Benzyldialkylamines
C,H,CH,NR,
H
A R,NH
+ C6H5CH3
Catalyst
The reductive debenzylation of N-benzyldialkylamines with hydrogen
in the presence of a platinum or palladium catalyst affords a n excellent
synthesis for symmetrical and unsynmetrical secondary amines ."" la5' 444
The starting materials are readily available by dialkylation of benzylamine or by the nonoalkylation of alkylbenzylamines, which in turn are
prepared by the reduction of Schiff b a s e s (method 429). T h e method has
been extended t o the formation of hydroxy amines? amino esters,'47
and amino a c i d s .447
435. Ammonoly sis of Halogen Compounds
RC1 + NH3 -+ RNH, HCI
In t h i s manner, N,N-dimethyl-n-b~tylamine"~and N,N-dimethylphenethylamine400 are obtained in yields over 80% from the corresponding primary
amines. Higher aliphatic aldehydes do not respond a s satisfactorily a s
formaldehyde.
By means of a modification of the procedure, aromatic aldehydes may
be converted by the action of ammonium formate t o primary amines, e.g.,
benzylamine (6%) and p-methoxybenzylamine (23%).547
Methylation of diamines with formaldehyde and formic acid yields the
In most
tetramethyl derivatives, e.g., tetramethyldiaminobutane (92%).'"
instances, alkylation of amino a c i d s by t h i s same combination gives complex products, although a-dimethylaminobutyric acid c a n b e made from
the corresponding a-amino acid in 80% yield."3 Reaction of the readily
available amino alcohols like N-methylethanolamine and 2-isopropylaminoethanol gives the N,N-dialkyl derivatives O.' n
T h e direct conversion of halides t o prinary amines i s discussed here.
However, it i s usually much n o r e desirable to u s e one of the indirect
methods such a s method 437 or 452.
T h e reaction of ammonia with primary alkyl halides generally forms a
mixture of primary, secondary, and tertiary amines and even a certain
amount of the quaternary ammonium halide. Still, the method may be
profitable for obtaining primary amines if the halogen compound i s above
C, and e x c e s s ammonia i s employed, for then polyalkylation i s l e s s likely
and the products, having widely different boiling points, are more readily
separated. Thus n-butyl bromide and a large e x c e s s of ammonia in alcohol solution a t room temperature give a 47% yield of n - b ~ t ~ l a m i n e : ~
In general, primary alkyl halides react better than secondary; tertiary
halides undergo d e h y d r ~ h a l o ~ e n a t i o nHigh-molecular-weight
.
alkyl
halides are slow t o react and must b e heated with alcoholic ammonia.'5
Anhydrous liquid ammonia favors the formation of primary amines.g6 Aryl-
666
substituted aliphatic halides such a s the arylchloropropanes give 21-51%
yields of the corresponding a m i n e ~ : ~
Aryl halides react t o form largely primary amines. High-pressure ammonolysis at an elevated temperature (100-200') in the presence of a
copper catalyst is r e q ~ i r e d . ' ~ ' " T h e Phalofluorenes take an anomalous
course:'
Heterocyclic amines are quite often prepared by ammonolysis of
- ' ~ halogen atom in 9-chlorothe halides over a copper ~ a t a l ~ s t . P ~ The
acridine is easily replaced by an amino group by heating to 120' with
ammonium carbonate and phenol?' Similarly, 2-chlorolepidine i s converted t o 2-aminolepidine (2amino-4-methylquinoline) (78%).P5 Aryl
halides in which the halogen atom i s activated by nitro groups are easily
converted t o the amines without catalyst, as in the preparation of 2,4dinitroaniline (76%)T3
Preparation of the simplest diamine, ethylene diamine, by ammonolysis
of the dihalide i s accompanied by the formation of diethylenediamine and
triethylenetetramine;98 other methods for its preparation are more suitable.
Only the higher homologs of P-dialkylaminoethyl bromide respond favorably to this treatment. Thus, di-n -butylaminoethyl bromide i s converted
t o the diamine in 55% yield whereas the dimethylaminoethyl bromide
undergoes extensive dimerization.P7 Trimethylene bromide reacts with
liquid ammonia to form trimethylenediamine (50%);'~however, experimental details are lacking. When the two halogens in the dihalide approach one another in s p a c e as in tetra- and penta-methylene dibromides,
then nitrogen spiranes a r e the main products.P6
T h e exchange of halogen for the amino group i s important in the formation of other polyfunctional compounds, particularly the amino acids. In
several of these transformations with aqueous or liquid ammonia, it h a s
been shown that the presence of ammonium s a l t s minimizes the formation
of secondary and tertiary a m i n e ~ . ' ~ ~ ' Excellent directions for the synthesis of a-amino a c i d s (C,€,) from U-halo acids and ammonia are
given, I O ~ - I I O The methods have been r e v i e ~ e d . ' ~ 'lo3
~ Long-chain amino
acids are prepared by t h i s and other procedures."'
Other a s p e c t s of the ammonolysis process have been d i s c ~ s s e d . " ' ~55s
'
436. Alkylation of Amines
R'X
R'X
RNH, -+ RR'NH --+
RR'J
HX
667
METHOD 436
Ch. 24
AMINES
T h e direct alkylation of a primary amine with an alkyl halide results in
the formation of secondary and tertiary amines in varying amounts, depending on the conditions of the reaction. Quite often, these products
are accompanied by unchanged amine and quaternary ammonium salt. As
in the ammonolysis of halides, formation of a particular product is favored
by employing a large e x c e s s of one reactant: e x c e s s alkylating agent for
the tertiary amine or e x c e s s amine for the secondary amine. The reaction
i s important in the synthesis of aromatic secondary and tertiary amines
as well as some aliphatic tertiary amines. Thus, in the synthesis of
N-phenylbenzylamine, a n unusually high yield of this secondary amine
(96%) i s obtained with a 4 :1 molar ratio of aniline t o benzyl chloride.l14
Other N-monoalkylated anilines are obtained in a similar manner (7585%).11' Also, certain ~ a r y l e t h y l a m i n e s ArCH,C&NHR,
,
are prepared
from P-arylethyl bromides and primary amines by using a large e x c e s s of
the latter."'
Very often, alkylations of this nature which are carried out
in aqueous ethanol are accompanied by hydrolysis and alcoholysis of the
halide:6
Some N-alkylated aryl amines like N-ethylm-toluidine may be
synthesized in fair yields from reactants which are present in equimolar
quantities (66%).11'Conditions for the exclusive formation of N-methylaniline from chlorobenzene and methylamine have been found."7
C,H,Cl
+ 2CH,NH, % C6H,NHCH3 + CH3NH,.
HCI
Heat
Such a process parallels that for making aniline from chlorobenzene and
ammonia and involves a copper catalyst which promotes the reaction of
the aryl halogen atom.
Sometimes the degree of alkylation can be controlled more carefully by'
employing other alkylating agents. Thus, primary amines may b e alkylated t o secondary amines free from tertiary amines by the action of
aluminum alkoxides a t 250-350' in a sealed tube. The procedure is illustrated by the treatment of aniline with aluminum ethoxide a t 275' t o
form N-ethylaniline (94%)F6 On the other hand, alkylation with alkyl
phosphates leads t o tertiary amines, e.g., N,N-diethylaniline (99%) and
N,Ndi-n-buty laniline (79%)."lg l'' T h e s e reagents afford a simple and
convenient procedure furnishing yields in the range of 53% t o 95%. Other
alkylating agents for the formation of dialkylarylamines include the e s t e r s
of sulfuric, sulfurous, and p-toluenesulfonic acids."'
It has been noted
, that pyridine a c t s as a catalyst in the production of N,Ndimethyl-anaphthylamine from a-naphthylamine and dimethyl s ~ l f a t e . " ~
Commercial processes for obtaining the N-alkylated anilines are based
on the reaction of aniline s a l t s with alcohol in a n autoclave a t about 200'.
A laboratory adaptation of this application of an alcohol a s the alkylating
668
AMINES
METHOD 436
Ch. 24
agent c o n s i s t s in heating the alcohol and aniline with a small amount of
iodine in an autoclave for 10 hours a t 220° t o 230°. In this manner, either
mono- or di-alkylated anilines are prepared (60-90%).'35 Other c a t a l y s t s
include copper and sodium halides.'OO The mono- and d i a l k y l a t e d amines
may be separated by treatment with a c e t i c anhydride and d i ~ t i l l a t i o n . ' ~ ~
Aliphatic tertiary amines are prepared by the interaction of secondary
amines and alkyl bromides. Equimolar quantities of the reactants are
treated in alcohol solution in the presence of a n inorganic b a s e for 2 t o
6 days a t room temperature or more quickly in an autoclave a t a higher
temperature. Many compounds have been characterized; however, the
yields are not always ~ t a t e d . ~ " * " ~N-Alkylated benzylamines are commonly prepared by this pr~cedure;"'~ 'l5* t h e s e compounds are important intermediates in the synthesis of pure secondary amines (method
434). Alkylation of diethylamine with isopropyl bromide has been accomplished, after many unsuccessful attempts, by heating the reactants
under reflux in glycerol solution for 72 hours (60%).Ia6
Preparation of aromatic secondary and tertiary amines like diphenyland triphenylamine i s catalyzed by copper powder.'36
Further alkylation of tertiary amines yields quaternary ammonium s a l t s .
T h e s e compounds are numerous and are readily prepared by heating the
alkyl halide and tertiary amine in the absence of a solvent or in the
presence of a l c ~ h o l . ' ~ ~ - ' ~Methylation
'
of tertiary amines t o quaternary
ammonium s a l t s can be accomplished with methyl h a l i d e ~ ' ~or~di~ ~ ' ~
methyl ~ u l f a t e . ' ~ ~
Monclalkylation of e t h y l e n e d i a m i ~ ewith high-molecular-weight alkyl
chlorides and bromides (C, t o C,,) c a n be successfully carried out when
a highly concentrated solution (95%) of the diamine is employed. The
N,N-Dialkylethylenediamines,
);ields are in the range of 83% t o
R,NCH,CH,NH,, are prepared by other methods (methods 427, 435, and
452). sym-N,N'-Dialkylethylenediamines, RNHCH,CH,NHR, may be obtained either by the treatment of ethylenediamine with two moles of
halide (84-90%)145 or by the reaction of ethylene chloride with a n e x c e s s
of the primary amine in a n autoclave, as in the preparation of N,N'-din-butylethylenediamine (50%).'46 Other alkylated diamines are formed by
the amination of dialkylaminoethyl ~hloride."~'14' In some instances, a
copper-bronze catalyst has been employed;'48' '49 the yield of diethylaminoethylaniline from the alkylation of aniline by diethylaminoethyl
chloride is increased from 72% to 88% with this catalyst.'49 A copperbronze or cuprous chloride catalyst i s more frequently employed in the
condensation of aryl halides with a m i n e ~ . ' ~ '
Alkylation with allyl halides gives olefinic amines .'?
Halo amines are formed by these procedures. Partial amination of a i methylene chlorobromide with diethylamine yields l-dieth~lamino-3-
669
chloropropane (70%) accompanied by the formation of diethylamine hydrobromide.'53 Halo anilines respond t o the usual treatment with dimethyl
alkyl h a l i d e ~ , 'or~ ~alkyl phosphates .l3'
sulfate ,"Ov
Amino alcohols are commonly made by the amination of halo alcohols
or by alkylation of amino alcohols. Thus P-diethylaminoethyl alcohol i s
synthesized from diethylamine and ethylene chlorohydrin (70%).'*
Higher
NO is omerization
amino alcohols are made in a similar manner .'52' '65-'68
through the formation of an ethylene oxide intermediate occurs during the
~
s e r i e s of alkylaminoalkylcarreaction of a 1 , 2 - ~ h l o r o h ~ d r i n . ' ~Several
binols, RNHCH,(CH,),OH, have been prepared by alkplations of ethanolamine (16-53%),'57 2-amino-2-methyl-1-propanol,and 2-amino-l-b~tanol.'~'
For the preparation of mixed N,N-dialkyl derivatives, better yields are
Aliphatic
obtained when the larger alkyl group is introduced first.'60*
tertiary amino alcohols of the type (CH,),COH(CH,),N(CH,~, n = 1 to 4,
have,been prepared by amination of the corresponding bromohydrins
(52%).'6'
The latter compounds are readily obtained by the action of
methylmagnesium bromide on bromo e s t e r s (method 91). The alkylation of
2-amino-2-methylpropanol with tetramethylene bromide leads t o 241pyrrolidy1)-2-methylpropanol (76%).16'
Amino ethers are obtained by the same reactions employed for amino
.'51.
170-174
Aliphatic and aryl aliphatic amino ketones are made by the amination
of the halogenated carbony l compounds ,'78-1as e.g., dimethylaminclacetone
(74%),'78 1-diethylamino-2-penmnone(79%),536 and a-methylaminopropiophenone (57%).'05 It i s noteworthy that this system may undergo a rearrangement, viz., ArCOCH,Br + (C,H5XNH -4 ArCH,CON(C,H5), (45%).539
The reaction of a-halo ketones with arylamines is even more complex.540
Examples of the formation of a-aminoaldehydes by this method are few.'75
However, the same results may be achieved by the amination of the halo
acetals with subsequent h y d r o l y s i s ~ 8'76*
' '77
Amination of halogenated acids or e s t e r s i s possible.'87-'9'
When
circumstances are favorable, dehydrohalogenation occurs, a s in the treatment of ethyl a-bromoisovalerate with diethylamine; the product i s Fedominantly the a,P-unsaturated ester."'
The amination of aliphatic
chloro and bromo nitriles i s facilitated by the presence of potassium
iodide .193-196 Halogen atoms in the o- and p-nitrohalobenzenes are readily
670
Ch. 24
AMINES
replac'ed by the dialkylamino group, a s in the preparation of p-nitrodimethylaniline (97%).'"* '"
-
437. Interaction of Hexamine and Halogen Compounds
RX
+ (CH2),N4
(CH,),N4 RX
H
RNH,
sHCI + NH,CI
The interaction of alkyl halides, preferably iodides or bromides, with
hexamine in chloroform or alcohol solution forms quaternary ammonium
s a l t s which on heating with hydrochloric acid are readily converted t o
primary amines'4l'.
The procedure has been employed successfully
in the reaction of primary, but not secondary or tertiary, aliphatic halides,'% 236 certain benzyl h a l i d e s ~ " *'" halo ketones,"' halo acid^,"'^ '"
'"
.
METHODS 439-441
Certain aromatic and heterocyclic compounds having reactive nuclear
positions undergo direct amination. Thus a-nitronaphthalene on treatment
with hydroxylamine in methanolic potassium hydroxide yields 4-niuo-lnaphthylamine ( 6 0 % ) y 7 following the rules of orientation for substitution
by a nucleophilic reagent rather than an electrophilic reagent.
The amination of heterocyclic b a s e s s u c h a s pyridine, quinoline, and
their derivatives by alkali amides furnishes a good method for obtaining
the 2 a m i n o compounds (50-100%). The scope and limitations of the
reaction have been reviewed; the procedure i s illustrated by the preparation of 2-aminopyr idine (76%).'08
440. Rearrangement of N-Alkylanilines
and halo e s t e r s .'40* 24' T h e yields range
from 40% t o 85%.
Certain quaternary ammonium s a l t s , particularly the hexaminebenzyl
halides, form aldehydes when heated with water (method 147).
438. Replacement of Hydroxyl Groups by Amino Groups
(NtG)aS03
Cl0H7OH + NH, \ Cl0H7NH, + H,O
T h i s equilibrium reaction in the presence of sulfites i s important f a
the preparation of certain polyfunctional benzenes and naphthalene
derivatives bearing hydroxyl or amino groups (cf. method 94)(Bucherer).
A review of the literature t o 1342 has been made.'"
T h e hydroxy compounds are converted t o the corresponding primary amines by treatment
with aqueous ammonia and ammohium sulfite a t 90-150°, good mixing
being essential, a s illustrated by the preparation of 2-naphthylamine (96%)
In a similar manner, r e s u c i n o l
and 7-methyl-l-naphthylamine (90%):"
and its alkylated derivatives have been changed t o the corresponding
amino phenols (5 0-80%)."Os "' Benzene derivatives containing one hydroxyl or one amino group a r e much l e s s reactive. Hydroxyquinolines
undergo this reaction (65-8~%).'~" 393* 646
Sometimes, replacement c a n be effected by heating with ammonia under
pressure in the presence of zinc chloride, e.g., 3-amino-2-naphthoic acid
from 3-hydroxy-2-naphthoic acid (70%)."'
439. Amination of Aromatic Nuclei
6 71
C6H,NHR
P-RC6H,NH,
Heat
Treatment of N-monoalkylanilines with anhydrous cobalt chloride a t
about 220' for 13 hours c a u s e s a nitrogen-to-carbon rearrangement t o form
p-alkylanilines
Normal alkyl groups migrate without a.pparent isomerization within the group to give good yields (60-85%); however, sand t a l k y l a n i l i n e s undergo extensive decomposition t o give olefins and
aniline. Similar treatment of the aniline s a l t s gives the rearrangement,
viz., N-isobutylaniline HCI -4p-amino-t-butylbenzene. In this c a s e ,
isomerization oizcurs within the alkyl group.
.
441. Amination of Cyclic Imines
N-Alkyl- and N,N-dialkyl-ethylenediaminesare prepared in a single s t e p
(cf. methods 427, 435, and 452) by the addition of gaseous ethylenimine
to primary or secondary m i n e s in the presence of anhydrous aluminum
chloride (77-89%).4" Primary m i n e s react a t about N o with benzene a s
solvent, whereas secondary amines react a t 180° with tetralin or biphenyl
a s solvent. In a similar manner, homologs of ethylenimine and ammonia
(or amines) react in high-pressure equipment a t loo0 in the presence of
ammonium ch10ride.'~~
AMINES
Ch. 24
442. Amination of Oxides
/O\
CH, CH,
-
+ R,NH
The addition of aliphatic and aromatic amines to other unsaturated ketones
has been discussed.'.75 a$-Unsaturated aldehydes like acrolein and
cmtonaldehyde combine with two moles of amine to form unsaturated 1 , s
diamines, RCH(NR,)CH=CHNR,.'53 The addition of primary or secondary
amines to acrylic esters has provided a good route to the N-alkyl-P-aminoThe product may add a second molecule of ester
propionic
to furnish alkyl di-(carbalkoxyethyl)-amine~;'~' however, the course of
the reaction can be controlled in many instances to provide largely the
secondary or tertiary amine.
-+ R,NCH,CH,OH
Ammonia and m i n e s open oxide rings to form amino alcohol^;'^"'^^ the
yields are markedly higher when amines are employed ( 5 5 9 0 % vs. 1840%).464.*67.468 The ready availability of ethylene and propylene oxides
makes this procedure attractive for preparing 2-dialkylamin~ethanols'~'
and l-dialkylamino-2-propanols.'6'
Thus P-diethylaminoethanol i s conveniently prepared by the addition of ethylene oxide to diethylamine in
methanol at 45' to 60° or by a combination of the two reactants in an
autoclave at 100' (81%)." Isopropylamine reacts with ethylene oxide in
the presence of water and a small amount of hydrochloric acid to form
P-isopropylaminoethanol (76%).'63 The reaction i s general and i s shown
by higher oxides like isobutylene ~ x i d e , ' ~ styrene
'
oxide,'68 and stilbene
oxide.'69
-
RNH,
RaNH
* [R,NCH=CH,]
Catalyst
H C 3 CH
R,NCH(CH,)C
CH
Acetylene and either primary or secondary aliphatic amines react under
pressure at 80' to 100' in the presence of a copper catalyst to form Nmono- and N-&-substituted 3-aminobutynes, e.g., 3-diethylamino-I-butyne
(65%).'7a Although benzylamine responds favorably, aniline and acetylene
furnish only a 25% yield of 3anilino-l-butyne.
The treatment of ally1 alcohol with amines in the presence of an equimolar quantity of alkali in an autoclave at about 115' represents a
general method for the preparation of N-alkyl-3aminopropanols, e.g.,
3-dimethylamino- l-propanol (65%)."'
C& =CHCYOH
R NH
R,NC&C&C&OH
NaOH
Ammonia and amincs add more easily to a double bond which i s conjugated with a carbonyl or carbalkoxyl group to form &amino compounds.
Thus, mesityl oxide and aqueous ammonia react under mild conditions to
form diacetonamine (70%).47'
CHl-
CHCOS'
+
cy-
RNHCH,C&CO,R'
CHCO,R' +
Other a#-unsaturated esters including methyl m e t h a ~ r y l a t e , 'ethyl
~~
crotonate,"' and ethyl cinnamate"' respond to this treatment. Ammonia
adds to ethyl crotonate to form a 55% yield of ethyl P-aminobutyrate; on
the other hand, the interaction of ammonia and ethyl acrylate produces
only di- and tri-substituted product^.'^'
Amination of a,&unsaturated acids i s brought about by treatment with
two moles of hydroxylamine in alcohol solution, a s illustrated by the
acid (34%).'8'1'86
synthesis of dl-~-amino-~-phenylpropionic
443, ,Amination of Unsaturated Compounds
HC=CH
673
METHODS 443-444
C,H, CH(NH,)CH, CO,H
\
l
l
l
~
The interaction of ammonia or amines with a-nitro olefins,
RCH=CHNO,, in alcoholic solution at 0' forms nitroamines, e.g.,
l-nitro-2-aminopropane (55%) and 2-nitro-3-aminobutane (60%). The reaction is general and is applied to numerous nitro olefins readily obtained
by the dehydration of aldehyde-nitroparaffin condensation p ~ o d u c t s . ' ~ ~ * ' ~ ~
l
~
RCH =CHNO,
+ NH,
-4
444. Arninomethyla tion (Mannich)
l
RCOCH,
+ CH,O + (CH,),NH
HCl
RCH(NH,)CH,NO,
-
-H,O
RCOCH,C&N(CH,)a
HCI
Compounds possessing labile hydrogen atoms readily condense with
formaldehyde and an amine (primary or secondary) or ammonia, thereby
placing an aminomethyl or substituted aminomethyl group at the location
674
of the reactive hydrogen atom. The reactive hydrogen may be present in
"~
ester, or nitrothe alpha position of an a l d e h ~ d e , " k~ e t ~ n e , ~ ~ " acid,4a4
paraffin;sg.~.4as.4a6
or it may be in the ortho or para position of a phenol4"
or in certain heterocyclic corn pound^.^^^"^^
Secondary products are often formed by the replacement of a second
active hydrogen with an aminomethyl group.
HC1
RCOC\CH,N(CH,),
* RCOCH[C\N(CH,),
CH~O
HCI],
(CH3)aNH' HCl
Also, Mannich bases which are themselves primary or secondary amines
may undergo further condensation to yield tertiary amines.
RCOCH,CH,NHR
HC1
CH,O
METHODS 446--447
Ch. 24
AMINES
> (RCOCH,CH,),NR
HCI
+ H,O
RCOCH,
The literature of this reaction to 1942 has been reviewed."'
Later
observations have been made.'""a'*51'
The synthesis of P-dimethylaminopropiophenone (72%) exhibits a typical procedure."'
poor for the higher amines because of the formation of the corresponding
In ~order
nitriles and acyl alkyl u r e a ~ . ~ ' ~
' ~ to overcome this difficulty,
the high-molecular-weight aliphatic amides are treated with bromine and
sodium methoxide with subsequent hydrolysis of the resulting u r e t h a n e ~ . " ~
RCONH,
+ Br, + 2NaOCH, 4 RNHCO,CH, + 2NaBr + CH,OH
Alicyclic amines have been produced by the same modifi~ation."~~"'
A few diamides have been converted to d i a m i n e ~ . ~ ' ~ ~ ~
For
' * the
'~~
most part, the conversion of unsaturated amides is unsatisfactory; however, a-allylphenylacetamide is transformed to a-allylbenzylamine in a
90% yield.16' Aromatic amides having free or methylated phenolic groups
are treated preferably with sodium hypochlorite rather than hypobromite
Certain amino
in order to avoid excessive ring halogenati~n.~'~*~~'~~~~
acids like anthranilic acid and P-alanine have been synthesized from the
appropriate imides.16'
445. Aminmethylation of Alcohols
R,NH
675
(45% yield)
+ CH,O + R'OH
--, R,NCH,OR'
The interaction of paraformaldehyde, a secondary amine, and an alcohol
occurs vigorously t o form in good yields an aminomethyl alkyl ether.
The method is general and has been applied to the formation of many
amino ethers.'"
-
CH,CO,H
CH,CO
447. Degradation of Acyl Azides (Curtius)
446. Degradation of Amides (Hofmann)
RCONH,
NaOBr
RNCO
2 RNH,
Amides react with alkaline hypochlorite or hypobromite solutions to
form primary amines having one l e s s carbon atom. The reaction involves
the hydrolysis of an isocyanate, which i s seldom isolated. Isocyanates
are also intermediates in the Curtius and Lossen rearrangements (methods
447 and 448). Although these methods have a common mechanism and
intermediate, they involve three separate and distinct types of starting
materials and are, therefore, treated individually. A comparison of these
reactions has been made."'
A detailed discussion of the Hofmann reaction, which includes conditions, typical procedures, and compounds
prepared thereby, has been presented.'"
The method h a s been used for the preparation of aliphatic, aryl aliphatic,15'-"'
aromatic,"2s1" and heterocyclic l4,26Ov161,511.5'1 amines.
Yields for the lower aliphatic amines (C,-C,) are about 70-90% but are
The conversion of an acid to an amine of one l e s s carbon may be conveniently accomplished by way of the azide and rearrangement to the is*
cyanate. The azide may be obtained either from the acyl chloride and
sodium azide or from an ester by treatment with hydrazine and subsequent
diazotization. An excellent review including scope and limitations of
the reactions, selection of experimental conditions and procedures, and a
tabulation of compounds prepared thereby h a s been presented."'
The acyl azide undergoes a rearrangement similar to the Hofmann rearrangement (method 446) and to the Lossen rearrangement (method 448).
This step i s carried out in inert solvents like benzene and chloroform to
give the isocyanate directly or in solvents like alcohol and water which
will react with the isocyanate to form urethanes and ureas.
The amines are obtained by hydrolysis of any of these three inter* mediates. When hydrolysis i s impracticable, the alkylureas or urethanes
676
may b e converted with phthalic anhydride to alkylphthalimides which are
formed in excellent yields. T h e s e compounds a r e then readily decomposed by hydrazine according t o the usual Gabriel synthesis (method
4 52).272
0 + (RNH),CO --, 2
NR
+ CO, + H,O
T h e Curtius reaction can b e performed on a l i p h a t i ~ , " % a l i c ~ c l i c , ~ ~ ~ ~ " ~ * ~ ~ ~
aroma t i ~ , ~ " - ~or" heterocyclic 2"'283
azides.
T h e application of the procedure to azides containing other functional
groups h a s a l s o been described.lgO Diamines (from dicarboxylic
have been
a c i d s ),178-280 arylhaloarnines,28s~ and nitroarylamines
successfully prepared, whereas certain groups like the double bond, hydroxyl, carbonyl, and amino often cause the formation of products other
than the anticipated amine. For the synthesis of a-amino acids, the
readily a c c e s s i b l e alkylcyanoacetic e s t e r s may be employed as starting
materials. Their a z i d e s rearrange to cyano isocyanates, which can be
e a s i l y hydrolyzed.2"s "'
a-Amino acids may a l s o be obtained by applying the Curtius reaction to
substituted malonic acid e s t e r s a s in the preparation of ,8-phenylalanine
(44% o ~ e r - a l l ) . ~ " * ~ ' ~ ~ ~ ~ ~
7"
2 C6H5CH,CH
\
C6H,CH,CH
\
NaNO
FH
44%
-----3C6H5CH2CH
H+
CONNH,
CO2 C2Hs
METHODS 448-449
Ch. 24
AMINES
---4
\
CON,
677
Alkali s a l t s of hydroxamic acids and their derivatives undergo a rearrangement to give isocyanates. The method h a s had little synthetic
application; it h a s been re~iewed.'~'
449. Interaction of Hydrazoic Acid and Carbonyl Compounds (Schmidt)
(a)
RC0,H
(6)
RCOR
H SO
+ HN, U
RNH, + CO, + N,
+ HN,
H ,SO
-3RCONHR --, RNH2
The reaction of equimolar quantities of hydrazoic acid with an acid or
ketone affords a convenient method for preparing certain m i n e s . The
reaction is carried out by treating the organic compound in an inert solvent in the presence of sulfuric acid with gaseous hydrogen a ~ i d e , ' ~ ~
hydrazoic acid in solution, or sodium azide dire~tly.'~' An e x c e s s of
hydrazoic acid should b e avoided in the reaction of ketones, for then
tetrazoles are formed. It should b e recalled that hydrazoic acid is toxic
and explosive. A discussion of the method including scope and limitations, experimental conditions and procedures, and compounds prepared
thereby h a s been presentedz9'
Aliphatic,293 alicy ~ l i c , ' ~ and
'
aromatic acids 29"298 which are stable to
concentrated sulfuric acid undergo the reaction in good yields, although
detailed directions are frequently lacking. Amines prepared by this
single-step process are often obtained in higher yields than when prepared by either the Hofmann or Curtius degradation.*
Benzoic acids substituted with alkyl, halo, hydroxyl, alkoxyl, cyano,
or nitro groups react to give the corresponding substituted anilines in
41-80% yields.29s The carboxyl group in an a-amino a c i d d o e s not react
with hydrazoic acid; the reaction proceeds, however, if the amino group
is further removed. This difference in reactivity is shown by t h e conversion of a-aminoadipic acid to dl-ornithine (75%).,0°
+ HN3*H
H02C(CH2)3CH(NH2)C02H
H2N(CHJ3CH(NH2)C02H
The conversion of ketones to amides by the Schmidt reaction h a s been
mentioned elsewhere (method 362). Since the hydrolysis of the m i d e s s o
obtained proceeds readily, the two s t e p s provide a convenient synthesis
of amines from ketones. T h e yields are often higher than those obtained
from the Beckmann rearrangement with subsequent hydrolysis (method
448. Degradation of Hydroxamic Acids (Lossen)
RCONHOH
3 RNCO s
o
RNH, + CO,
Heat
*For a comparison of the Schmidt, Hofmann, and Curtius reactions, see ref.
270, p.
363.
678
Ch. 24
AMINES
451).29"299 T h e procedure is convenient for the synthesis of a-amino
acids from mono- or di-substituted acetoacetic e s t e r s (80-98%).3D1
450. Hydrolysis of Isocyanates, Isothiocyanates, Urethanes , and Ureas
RNCO
+ H,O
+ RNH,
ArNH,
CICO ,CH2CH2C1
have been employed for obtaining d i a m i n e ~ , ~ " * *unsaturated
~'
a~nines,*~'**~~
and amino acid^.*^^"^ The deacylation of p- and o-nitroacetanilides is
carried out with sodium ethoxide in boiling
Certain amines are conveniently prepared by the hydrolysis of Nsubstituted amides which are made by the Beckmann rearrangement (method
359) and the Schmidt reaction (method 362).
452. Hydrolysis of N-Substituted Phthalirnides (Gabriel)
+ CO,
Many important amines have been obtained by the hydrolysis of one
of t h e s e substances. Thus, t-butylamine is formed by alkaline hydrolysis
of t-butylurea (78%)*'* or by treatment of t-butylisothiocyanate with formic
acid (79%).*" Allylamine is synthesized by hydrolysis of ally1 isocyanate
with dilute hydrochloric acid (73%).''I
T h e hydrolysis of isocyanates,
urethanes, and ureas, which occur a s intermediates in the degradation of
amides and azides, h a s been discussed under methods 446 and 447, where
many examples have been cited.
6 - ~ r y l a m i n o e t h a n o l sare made by the condensation of arylamines with
chloroethyl chloroformate followed by treatment of the resulting carbamates with e x c e s s alkali. T h e reaction proceeds by way of an intermediate oxazolidone which need not b e isolated.458
ArNHCO,CH,CH,Cl
4
80%
In a similar manner, y-chloropropyl arylcarbamates formed from aromatic
amines and y-chloropropyl chloroformate are converted to y-arylaminopropan01s.''~
679
METHODS 451-452
COOH
CO
+ RNH,
CO
The facile alkylation of phthalimide and subsequent hydrolysis of the
N-substituted derivatives furnishes a convenient synthesis for primary
amines. T h e substituted phthalimide was originally prepared by heating
a mixture of phthalimide, potassium carbonate, and organic halide in a
non-polar solvent for 2 t o 24 hours at looo t o 1 5 0 ~ . * An
~ ~improved
procedure c o n s i s t s in performing t h i s initial s t e p in a polar solvent like
dirnethylformamide, in which potassium phthalimide is appreciably soluble;
the reaction occurs at room temperature within 10 minutes.429 Various
esters of p-toluenesulfonic acid may be substituted for the organic halides
a s alkylating agents.*)'
Tertiary alkyl halides l o s e hydrogen halide in their reaction with potassium phthalimide. However, the t-alkylphthalimides are readily prepared
by heating t h e corresponding t-alkylureas and phthalic anhydride to 200°
t o 240°.430
Hydrolysis may be carried out directly by refluxing the alkylated
phthalimide in b a s i c or acidic solutions or by the action of hydrazine
hydrate followed by a ~ i d i f i c a t i o n . ~ ~T'h i s procedure is illustrated by t h e
synthesis of t-butylamine (67% ~ v e r - a l l ) . * ) ~
451. Hydrolysis of N-Substituted Amides
T h e N-alkylation of amides followed by hydrolysis furnishes a good
route for making secondary amines. The f ~ r m y l , * ~acetyl,""
'
and arylsulfonyl
derivatives of amines are best suited for alkylation
(method 358). Hydrolysis is accomplished by refluxing concentrated
hydrochloric acid alone 3'*"'*4949*'497 or in acetic acid.'9a*s0a~So3N-Alkylformamides prepared by the addition of olefins t o nitriles (method 355)
are hydrolyzed with aqueous alkali.'06 Similar hydrolytic procedures
Alkylation with organic halides carrying a second functional group
affords a good synthesis of some difficultly obtained difunctional compounds including d i a m i n e ~ , ~ ' ~ ~ amino
* ~ ~ ' *halides,*)O
~~
hydroxy a m i n e ~ , " ~
amino k e t o n e ~ , ' ~ ~ ' *amino
* ~ acids,429~44"443amino cyanides,441~44s
and
680
n i u o .amine~.*~'Also t h e stability of the N-substituted phthalimide allows
further changes to be made, for example, (a) amination of y-bromopropylphthalimide with various secondary amines (60-80%),*'~ (b) catalytic reduction of N-(m-nitroben ~ y l > p h t h a l i m i d e ,(c)
~ ~ oxidation of &hydroxye ~ h ~ l ~ h t h a l i m i dand
e , ~ (4
' the action of halogen acids on epihydrinphthalimide.*'9
453. Hydrolysis of Nitrosaanilines
C,&NRR
,-. (HONO)
p-RR'NC,H,NO
RR'NH
+ pHOC6H4N0
This classical method for preparing secondary amines is rarely used.
It h a s been applied in the preparation of some a-dialkylamino-w -methylaminoalkanes (65-70%)."'
Higher yields have been obtained by hydrolyzing with sodium bisulfite rather than with sodium hydroxide, which
is the common reagent.
454. Hydrolysis of Quaternary Imine Salts
The alkylation of Schiff bases and hydrolysis of the resulting quaternary salts is an excellent method for obtaining certain secondary amines,
RR'NH, particularly where R'-= CH3.Z14 The procedure is l e s s satisfactory
for the introduction of large alkyl groups. The Schiff base is usually a
derivative of benzaldehyde. It is readily prepared, and, without isolation,
is alkylated; furthermore, the s a l t i s seldom isolated. An example is the
treatment of the Schiff base from allylamine and benzaldehyde. Methylation is accomplished by the action of methyl iodide a t 80° for 16 hours;
subsequent hydrolysis furnishes methylallylamine in 71% yield."'
455. Hydrolysis of Cyanamides
2
~
~
r R,NCN
~ *~H
' RzNH
~ +~CO, ~+ NH,
*
Examples include the synthesis of diallylamine (88%) and di-n-butylamine (75%)."'
456. .Ring Dehydrogenation
METHODS 456-460
Ch. 24
AMINES
68 1
Azines of certain carbonyl compounds like f methyl-Falkyl-2-cyclohexen- b o n e s and the alkylated l-teualones have been aromatized to the
corresponding fmethyl-5-alkylanilines and l-aminonaphthalenes by boiling with a palladium-carbon catalyst in t r i e t h y l b e n ~ e n e . ~The
~ ~ yields
in the first step are in the range 24% to 74% and in the second 20% t o
55%.
The nuclear amino group is stable during the sulfur dehydrogenation of
2-amino-9,lO-dihydrophenanthrene(cf. method 2).*." In another instance,
i t is protected by acetylation before dehydrogenation:91
457. Condensation of Grignard Reagents and (TMethylhydroxylamine
CH,ONH,
2RMgX
RNHMgX
2 RNH,
A general method for the preparation of primary amines, free from
secondary and tertiary amines, involves the interaction of Grignard
reagents and (Tmethylhydroxylamine. The yields range from 45% to 90%
for many amines including ethylamine (81%), t-butylamine (70%), namylamine (65%), and P-phenylethylamine (68%).'12
Grignard reagents which have been prepared from polymethylene halides
and magnesium in the presence of 0.1% water in the ether react readily
with 0-methylhydroxylamine to form the corresponding polymethylene diamines (50-68%).512
458. Addition of Grignard Reagents to Schiff Bases
ArCHO
ArCH=NR
R'hlg~
ArCH(RP)NHR
L
This method is particularly desirable when the stable and readily
available Schiff bases from substituted benzaldehydes are employed.
It furnishes a good synthesis for amines of the type ArCH(R')NHR where
the two R groups may be widely varied to include those from many Grignard reagents and primary aliphatic amines, e.g., N-methyl-1,2-diphenylethylamine (95%)*" and l-ethylamino-l-phenylbutane(90%):''
The reaction of aliphatic aldimines and Grignard reagents h a s been found to
proceed l e s s readily."'
459. Interaction of Grignard Reagents and Halo amines"'
RMgX + NH,U -+ RNH,
+ MgXCl or RC1 + MgXNH,
460. Reduction of Unsaturated A r n i n e ~ ~ ~ ' *(cf.
" ~ methods 431 and 443)
2HNR
RCH= CHCHO 4 RCH(N&)CH= CHNR, H'pPf*RCH(N&)CH,CH,N&
70-9370
682
Ch. 24
AMINES
-
T A B L E 81. AMINES
461. Interaction of Sodium Arnide and Halogen C~rnpounds'~~""
RX
+ NaNH,
L1 plid
RNH,
+ NaX
Arnrnonfa
R = n-hew1 (74%);M4 R = 2gyrIdyl
TABLE 81. AMINES
C,
Yield
Compound
Method
(%)
(67%)?a7
462. Rearrangement of H y d r a z o b e n z e n e ~ ~ ~ ~ * ~ ~ ~
5 HaNC6H4C6H4NH,
C6H5NHNHC6H5
C2
463. Interaction of Amines and P - ~ e t oEsters"'
RCOCH,CO,C,H,
R'NH a
b
RC(NHR') =CHCO,C,H,
4 6 4 Condensation of Unsaturated Amines and Aromatic Compounds496
CH, =CHCH,NH,
+ ArH
683
Ethylmine
Dimechylamine
C,
n-Propylamine
Isopropylamine
Trimethylamhe
C4 ~Butylamine
ArCH(CH,)CH,NH,
Isobutylamine
Methylisopropylamine
Teaamethylammonium
chloride
1Aminopenmne
3 Aminopenmne
Isoamylamine
Neopentylamine hydrochloride
For explanations and symbols s e e pp. xi-xii.
chapterref. B.p./mm., a;, ( u p . ) , Deriv.
684
685
T A B L E 81. AMINES
Ch. 24
AMINES
TABLE 8 1 (continued)
c,
Compound
(%)
chapterref. B.p./mm..
nb. (M.P.), Deriv.
Aliphatic Amines (c~ntinued)
C 5 Methybn-butylamine
Ethykn-propylamine
N,N-Diethylmethylamine
C6 ~ H e x y l a m i n e
lMethyl-4aminopentane
2,lDimethyl-3 aminobutane
Ethyl-n-butylamine
Dimethyl-n-butylamine
Triethylamine
C,
Method
~Heptylamine
2-Aminohep tane
n-Propyl-n-butylamine
Isopropyl-n-butylamine
Diethyli sopropylamine
n-Butyltrimethylammonium
bromide
C O Ethyl-n-hexylamine
Di-n- butylamine
C
Di-n-hexylamine
429
428
429
431
26t
53
43t
92
24369
24'"
24'24'"
91/750, 1.4011
78, 223HU
80/738, 1.3966, 224HU
185Pi
427
446
449
461
431
431
70
70
75
74
55
51
241m
24'4
24'24'24M
24=
130
128
126Pi
109, 1.4063'~, 139HU*
102, 297HC1
429
432
428
52t
80
50
24'241U
241U
109/737, 1.4056, 197HC1
94
89
426
426
427
431
446
449
426
431
432
429
429
436
436
64
73
95
63
65
75
80
80
55
54t
52t
60
93
24'"
24lW
24'24=
24w
24'9'
24'24'24=
24'24'24lS
24U9
153
15>157
58/23, 122Pi
156
119Pi
142.5
142. 1.4150'~. 83HU
142.5
93/200, 1.4112, 268HU
125/748, 1.4050
108
( 198)
434
455
434
76
75
24'"
2424'"
158/743, 191HU
160
122/15, 2 7 0 H a
lob
~
ane
4Methyl- l-aminocyclohexan e
PCyclohexylethylamine
amin e
N-Ethylcyclohexylamine
C9
l-Cyclohexyl-laminopropane
P Meth yl-pcyclohexylethylamine
N-Methyl-pcydohexylethylamine
Clo ~ h m i n o d e c a l i n
C,, Dicyclohexylamine
50t
80
24'w
24U
50/750, 149Pi
C6
426
426
430
431
432
449
60
90
94
50
75
82
24'2424'"
24'm
2dS4,
24'94
135
48-52/30,
446
77t
24"'
150, 1.457516, 147Bz
C,
Cydohexylamine
>Methyl-l-aminocyclohexane
m
aapter'ef.
~.p./mm., nb, (M.P.), Deriv.
446
90
24'"
150/743, 1.4535 l', 260HC1
430
426
79
80
24'"
24'"
85/25, L4656. 2 5 6 H a
151/745, 65/17, 198Pi
430
91
24=
165/745
430
77
24'"
87/21, 1.4615, 1 9 2 H a
430
86
24"'
91/17, 1.4718, 1 % ~ d
430
85
24'"
78/9. 1.4586. 172HC1
425
430
431
73
95
70
24'
2414
24''
92/12, 1rlSBz
145/30
llF120/10, 333Ha
C6
Aniline
425
447
449
86
76
85
24'
24"'
24'94
184, 1 9 5 H a
ll5Ac
C,
Benzylamine
426
427
427
431
432
435
437
446
447
449
451
452
457
431
436
436
425
425
425
73
72
69
89
60
53
84
85
94t
75
81
75t
57
24'24=
2424"
24s47
24%
2424'"
24'"
2dao4
24'"
24U'
24'"
24'"
24'"
24*'
244
24-'
244
74/15
N-Methylaniline
1.4569",
(
Aroma tic Amines
Alicyclic Amines
446
426
Yield
Alicyclic Amines (continued)
ttms 1Ethylcyclohexyl-
C , Cyclopropylamine
C 5 Cyclopentylamine
Method
Compound
206HU
o-Toluidine
m-Toluidine
p-Toluidine
50
90
73
73
25t
91
For explanations and symbols s e e pp. xi-xii.
85/24
80/8
182/680, 198Pi
75/14, lO5Bz*
184
184,258HCl
257HU
84/20, 60Ac
187, 60Ac
90/ 12. 194Pi
196.
IOlAc
199*, l l l A c
201/756, G5Ac
200a, 149Ac
6 86
Ch. 24
AMINES
T A B L E 81. AMINES
TABLE 81 (continued)
C,
Compound
Method
(%)
chapterref.
TABLE 8 1 (continued)
B.p./mm.,
nb. (M.P.),
this.
c,
Compound
Aromauc Amines (continued)
&Ethyl mtoluidine
Benzyldirncthylamine
N-Mcthyl-N-ethylaniline
N.N-dimethyl-mmluidine
N,N-Dimcthyl-p-toluidinc
P h cnyl Pimethylammonium
sulfete
FAminohydrindcne
2Methylarnino- l-phenylpropane
N-Ethyl-a-phcnethylaminc
N,N-Dimcthylphenethylamine
Denzylrnethylerhylamine
N,N-Diethylandinc
p-Dimcthylaminoethylbenzene
l-Naphthylamine
l-Phenyl- l-aminopmpane
2Phenyl- 1-aminopropane
2Naphth ylamine
l,2,3,rtTctrshydre2naphthylamine
C,,
a,a-Dimethylbenzylaminc
pn-Propylaniline
0-Isopropylaniline (pcumidine)
N-Methyl-a-phene thylamine
(%)
C m l-Phenyl-3-aminobutane
2 A m i n e 3-phenyl butane
o-Amino-l- butylbenzene
p- Amino-K-butyl benzene
2-Amino+-cymene
3,rtDiethylaniline
l-hkthylamine l-phenylpropane
l-Mcthylamine 2phcnylpropane
l , YDimethyl- F a m i n e
benzene
N- Ethylaniline
C9
Method
~ h a p t e r ~ eB.p./mm.,
~.
Aromatic Amines (continued)
C*
3-Amino- 1,Idimethylbenzene
&Amino- 1,ldimethylbenzene
687
l-Ethylamine2-phenylpropane
l-Dirnerhylamino-2
phenylpropane
2-Dirnethylamino- lphenylpropane
7-Methyl. l-naphthylamine
For cxplanations and symbols s e c pp. xi-xii.
n;, (M.P.). Deriv.
1
688
AMINES
T A B L E 81. AMINES
Ch. 24
TABLE 8 1 (continued)
p
'=?I
Compound
Method Yidd
~ h a p t e r ' e ~ . B.p./-..
(R
n b , (M.p.), Derir.
c71
- - --
Compound
N-Methylnaphthylamine
437
451
73
70
Cla p(a-Naphthy1)eQylamine
a-(,&Naphthyl)ethylamine
N-Ethyl-a-naphthylamine
N-Ethyl-pnaphthylamine
N,N-Dimethyl-a-naphthylamine
N,N-Emethyl-pnaphthylamine
2-Aminotiphenyl
fAminotipheny1
4Aminobiphenyl
o-Aminocydohexylbenzene
fAminoacenaphthene
447
432
431
431
436
45t
84
88
64
70
436
64
425
425
425
425
425
93
99
93
85
85
C,,
426
432
427
423
436
451
431
425
426
432
452
87
96
60
97
87
40t
65
82
74
75
87t
Benzhydrylamine
o-Phenylbenzylamine
N-Phenyl benzylamine
(benzylaniline)
N-Phenyl-p-mluidine
Methyldiphmylamine
2-Aminofluorene
~Aminotluorene
C14 P,PDiphenylethylamine
Dibenzylamine
m-Tolyl benzylamine
Erhyldiphenylamine
%Dimethylaminobiphenyl
N,N-Diethyl-a-naphthylamine
l-Aminophenanthrene
Method
(7.)
c h a p t e P f . B.p./mm,
Aromatic Amines (codinued)
Aroma tic Amines (continued)
C,,
Cl'
689
P,yDiphenylpropylamine
y,y-Diphenylpropylamine
N-Methyl- 1.2-diphenylethylamine
FAminomethylphenanthrene
Cl@ Triphenylamine
C,, p-Aminoteuaphenylmethane
427
427
458
88
81
95
24"'
24'"
244'0
427
435
100
70
24JU
24"
436
1
85
74
24"
24'"
Heterocydic Amines
C, ZAminofuran
CS Furfurylamine
%Methyl-3 aminohran
2-Methylaminofuran
2-Tlenylamine
a-Thienylaminomethane
2-Aminopyridine
f Aminopyridine
C6 N-Methylfurfurylamine
l-(a-Thienyl) laminoethane
,&(>Tlienyl)ethylamine
For explanations and symbols s e e pp. xi-xii.
ntD. (Up.). Deriv.
AMINES
Ch. 24
TABLE 81 (continred)
c,
Jd
Method Yi(7%)
Compound
Chapter'ef. B.p./mm..
TABLE 8 1 (continued)
n tD. (M.P.), Deriv.
c,
Compound
Heterocyclic Amines (continued)
2Dimethylaminomethylpyrrole
a-(Ethy1amino)-pyridine
C O l-(a-Furyl)3aminobutane
N-Ethyl->methylfurfurylamine
NJU-Dimethyl-5-methylfurfurylamine
,B-(3Pyridyl)-isopropylamine
y-Pipaidinopropylamine
3- Aminothianaphthene
FAminothianaphthene
C9
N,N-Diethylfudurylamine
8-Piperidinoburylamine
2Aminoquinoline
3- Aminoquinoline
691
T A B L E 82. DIAMINES
Method
(7%)
Chupter'ef- B.p./mm.,
Heterocyclic Amines (continued)
N,N-Diethyl-ppyridylmethylamine
2 Aminolepidine
428
435
78
24"
(133), 232Ac
C,,
f Dimethylaminomethyl-
444
100
24"'
(134). 142Pi
indole
2-Dimethylaminoquinoline
436
91
24U7
(7 1)
435
425
438
446
425
435
451
461
435
24
91
45
55
91
62
72
50
371
64
~ 4 ~ ' (74). 205Ac
24-l
(94)
24"'
(85).
24%'
24"
(133)
~ 4 ~ ' (129). 178Ac
24"'131)
24'"
(122).200Ac
~ 4 ~ ' (1 10), 198Ac
24"
(1 10)
60
89
39"'
39"'
l- Aminodi benzofuran
3-Aminodi benzofuran
4-Aminodi benzofuran
2Aminodibenzothiophene
fAminodibenwthiophene
4-Aminodibenzothiophene
Cl, 2Aminoacridine
PAminoacridine
....
....
435
24'*
-
C I,
C,,
55
n h , (h4.p.). Deriv.
100/12, 170Fi
(2 16)
(233)
For explanations and symbols s e e pp. xi-xii.
TABLE 82. DIAMINES
c,
Compound
Method Yidd
(7.)
chapterref. B.p.hm..
*b. @LP.), Deriv.
Aliphatic Diamines
C'
Ethylenediamine
447
452
75t
60
GAminoisoquinoline
cistrcas-Decuhydmquinoline
C,
,B-jTbianaphhylethy1amine
l-@Diethylaminoethyl)pyrrole
For explanations and symbols s e e pp. xi-xii.
24=
24"'
172Ac
116, 172Ac
692
AMINES
TABLE 82 (nmtinued)
TABLE 8 2 (nmtinued)
c,
Compound
Method
Yield
(%)
Chapterref. B.p./mm.,
n;,
(M.P.).
cm
Deriv.
Compound
2,f Diaminobutane
Isobutylmediamine
y-Methylaminopropylamine
N-Monoethylethyl-
425
427
427
451
40
80
70
201
24m
24'"
24'19
24m
3 lWCl
115/754*, 100Ac
141, 1.4479, 22GPi
131/759. W5Pi
l
C B l-Diethylamin*>aminobutane
l-Diethylamin* faminobutane
4-Diethylaminobutylamine
1,3-bisDimethylamine
butane
1,4-bisDimethylamine
butane
l-Diethylaminc-f
methylaminopropane
diamine
C S Pentamethylmediamine
(cadaverine)
2-Methyl- l,>diamine
butane
>Methyl- 1,4-diamin*
butane
Z,>Dimethyl-1,fpmpanedi ami ne
y-Ethylaminopro~lamine
l-Dimethylamin*>
aminopropane
C 6 Hexamethylenediamine
l-Ethylamin*>
aminobu cane
>Methyl->methylamin*
l-aminobutaae
f Ethylamino-2-methyl->
aminopropane
BDiethylaminoethylamine
C7
l-Diethylamin*>
aminopropane
~-Diethylamino~ro~~lamine
l-Dimethylamin*3methylaminobutaae
l,fbisfimethylamin*
propane
BDiethylaminoethylmethyl amine
457
68
24'=
180, 237Pi
427
611
24'=
143/752. 1.4483. 229Pi
446
72
24'"
154Bz
425
425
427
431
90
67
74
40
24'
24"
2419'
24"'
78/50, (29), 257HCla
153/737, 1.4566, 240Pi
156/735, 1.444 1, 193Pi
113. 1 . 4 1 7 7 ~
452
457
441
861
51
20
24U'
24'*
24W
258HCI
204, 220Pi
157, 1.4431, 116Bz
24'=
155/737. 1.4502, 203Pi
427
Method
(%)
~ h a ~ t e r r e fB.p./mm.,
.
nb, (h4.p.).
Derir.
Aliphatic Diamines (nmtinued)
&liphatic Diamines (continued)
C,
693
T A B L E 82. DIAMINES
Ch. 24
441
42
24U'
141, 1.4300, lO8Bz
427
427
441
452
53
62
89
57
24'M
24='
244U
24's
145/760, 99/ 13, 207Pi
144- 150, 2 1Pi
431
431
427
452
436
62
65
72
GO
100
460
78
436
40
1 4 F 149
C9
l-Diethylamin*3amino pen tan e
Teaaethylmethylenediamine
Clo Decamethylmediamine
l-Diethylamin*4aminohexane
,B-Diethylaminoethyldiethylamine
425
441
426
431
427
427
436
4G0
436
55
54
24"
2424'U
24'24'=
24'"
24"
24m
241U
80/ Ilj
173, 1.4347
74/12, 1.4428''
70/10, 1.4430"
88/ 18, 1.4462..
86/16, 1.4420"
56/ 12
72
97
50
100
74
92
453
65
24'"
60/8, t439019
426
75
24U*
86-95/22, 1.4421, 155Pi
....
76
24'U
167/757
427
426
80
64
24'=
24'"
146/ 14, (GO)
105-1 12/20
436
50
24'"
151Pi
GO
15GPi
167, 199Pi
Alicyclic Diamines
C 4 t r a n s 1,2-Diaminocycl*
butane
447
449
121
551
24"'
24"'
74/50, 1.4837
74/50, 1.4837
C,
430
447
450
447
60
501
100
72 1
24'"
24'"
24'"
24"'
265Pi
W8/760, 2 6 P i
198/7GO, 265Pi
427
331
24'"
115/8, 350HC1
427
22 1
430
63
24"'
87/11, 1.4767"
430
70
2419'
85/4, 1 . 4 7 2 0 ~
1,f Diaminocyclohexane
1,4-Diaminocyclohexane
C B cis-1,4-Diaminomethylcyclohexane
tr-l,4-Diaminomethylcyclohexane
N-Ethyl- 1.4-cyclohexanedi ami ne
Clo N,N-Diethyl-l,+cycloher
anediamine
118/10, (27), 380HC1
Aromatic Diamines
C,
o-Phmylenediamine
m-Phenylenediamine
sym-Tri amino benzene
425
425
425
85
95
76
For explanations and symbols s e e pp. xi-xii.
24U
2414
244
( 101)
154/10, 70Ac
(84). (112). 357Bz
694
Ch. 2 4
AMINES
TABLE 8 2 (c~tllirued)
c,
Compound
TABLE 83 (continued)
Yield
Method
~ h a p t c f l ~B.p./mm.,
~.
(9.)
")D,
(M.P.), Deriv.
Aromatic Diamincs (continued)
C,
C.
C,,
Cl'
C,,
o-Aminobenzylamine
m-Aminobenzylamine
2,ltDiaminotolume
symTriaminotolueac
425
452
425
425
43
28t
74
60
24"
24"
24U
24U
85-9W1, (59), 1 3 8 k
134/4, 16092, 174Bz
(9 S)
(122)
Phenylcthylencdiaminc
mXy lylendiamine
N-Phcnylaminocthylamine
p-Aminodimethylaniline
427
452
441
90
38t
89
24'U
2424&
159Ac
141/14, 135Ac
....
75
24"'
140/12, 13OAc
m-~henylen-P,P'diethylamine
p-~henylen-P,P:
dicchylamine
N-(ZDimethylminw
echy1)-aniline
427
79
24'-
161/14, N 2 H U
3,3'-Diaminobiphenyl
4,4'-Diminobiphmyl
(bwzidine)
4,d-Diami~odiphen~lmechane
C,,
p,pcbis-~minomethyltiphenyl
Cl' p,p'-bis- hinomethyldiphenylmethane
695
T A B L E 85. HALO AMINES
!
75
24'=
116/0.9, (36), 2lOAc
436
88
24"
127/3, 1.5251",
425
425
95
82
2414
24U
(125)
....
70
24-
(91). 237Ac
124HU
n;,
(h4.p.). Deriv.
Compound
Method
C,
l-Dimechylamino-bpmtme
Allyldiechylamine
pAminostyrene
29
436
19
80
84
20
19s
24"'
2'-
118/750, 1.4202"
111, 1.4170m, 91Pi
79/2.5. 1.6070a'
l-Dicchylamino-bpentene
29
19
451
85
87
63
19s
2'"
2449'
156/746. 1.4310
87/2, 1.5676"
80/2
425
72
W)
69
89
81
C.
C9
~(o-Aminopheny1)-propene
N-Allylaniline
427
chapterref. B.p./mm..
c,
C,, cisp Aminostilbmc
t r m p Aminostilben c
ciso.0'-~iaminortilbene
cisp.p'-~iminostilbmc
trunsp,p'-Diaminosdl bene
cis-pep'-~iaminostilbene
trmmp.p'-Diaminostilbenc
30
425
(7.)
For explanations and symbols s e c pp. xi-xii.
TABLE 84. ACETYLENIC AMNES
'%
427
80
24"
180/0.5, (145). 235Pi
427
80
24'"
(90). 22482
For explanationr and symbols s e e pp. xi-xii.
Method '"ld
(So) d a P t & e f .
Compound
C,
C,
C,
3-Dimcthylamino-l-hwne
l-Diechylamino-2-propyne
fDiethylamino-l-bucync
l-Dicthylamino-2-hwne
C,, fDiethylamino- l-phenyl-lpropyne
C,, p,p'-~iaminotolane
~.p./mm., n;,
( ~ p . ) ,briv.
443
43
443
44
444
63
83
65
74
80
24,,'
3"
24,,'
3 ss
244U
95
120, 1.42%"
126, (10). 1 7 9 H a
153, 1 . 4 4 1 3 ~
137/18. 137HC1
425
60
244
(235). 28lAc
For explanations and aymbolr s e e pp. xi-xii.
c,
C,
C,
Compound
Nlylamine
Methallyl m i n e
Allylmethylamine
Method
450
435
450
451
454
Yield
(%)
73
70
35
48
71
TABLE 85. HALO AMINES
Chapterref. B.p./mm.,
24U6
24'"
244n
2424'*
n;,
(M.P.), Daiv.
57/746
78.8, 1.431
62, 1.4155, l58Pi
65, 1.4065
64
c,
Compound
Mcchod
Yield
C h a p t a n f . B.p./mm.,
t
nD, (M.P.), Deriv.
Aliphatic and Alicyclic Halo Aminer
C,
PBromocthylamine
P-Iodoehy laminc
N-Tetrachloro- 1,2diaminocthane
51
52
....
83
72
80
51
69
92
77
For explanations and symbols see pp. xi-xii.
4
4"'
24'=
4
4-
.
173HBr
(174)
78/10, (4.5)
AMINES
Ch. 24
T A B L E 85. HALO AMINES
TABLE 85 ( c o n t i m e 4
c,
Compound
Method 'liddchapterref. B.p.hm.,
(%)
TABLE 85 fantim+)
n tD. (Mp.). Deriv.
GB
Aliphatic and Alicyclic Halo Amines (continued)
C,
C4
C,
l-Amino-2- bromopmpaoe
'y-Bromopropylamine
Isopropyldichloroamine
2-Chloroethylethylamim
P,,B'-Dichlorodiethylamine
P-Dimethylaminoethyl
chloride
pDimethylaminoethy1
bromide
I- Burylchloroamine
n-Butyldichloroamin e
N-Chlorodiethylamine
hexane
l-Diethylamina- fchlorobutane
CP
l-Dimethylamino- f
chlorobutane
PDiethylaminoethyl
chloride
PDiethylaminoerhyl
bromide
P,P ',P"-~richlorouiethylamine
o-Chlorn~~dohexylamiae
o- Bromocycloh exylamine
Cyclohexyldichloroamine
C,
l-Methylamino-6
bromohexene
l-Diethylamino- 2-chloropropane
l-Diethylamino-f chloropropane
-
Chapterref- B.p./m.,
----
4 174
53
436
87
68
53
72
24'"
4 174
73
30
4-
54
98
n b , (M.P.), Daiv.
73
75
4-
~
o-Aminobenzyl chloride
o-Aminobenzyl bromide
4-Amino-f chlorotoluene
l-Phmyl-l-amino-2chloroethane
N,N-Dimethyl-o-chloroaniline
N,N-Dimethyl-o-bromoaniline
For explanations and symbols see pp. xi-xii.
72/17, 82HC1
84HC1
87/18
67/5
377
Aromatic Halo Amines
C8
EDiethylamino- l-chloiopropane
f Bromopropyldiethylamine
l-Diethylamina-f chlorapentane
l-Dierhylamino-tchloropentane
Clo l-BromwGdiethylaminohexane
1-Diethylamina-tmethyltchloropenrane
l-Dimethylamino-2chloropropan e
l-Dimethylamino- f
chloropropaoe
1Dimethylamina- 1chloropropane
f Bromopropyldimethylamine
C6
Yield
Aliphatic and Alicyclic Halo Amines (contimedJ
52
452
69
53
53
Method
Compound
65/3, 1.4459
698
AMINES
I
Ch. 2 4
TABLE 85 (wtllinued)
c,
Compound
Method
Yield
(%)
chapterref.
B.p./nun.,
n
L, (M.P.),
Deriv.
TABLE 86 (continued)
C,
N,N-Dimethyl-mchloroaniline
N,N-Dimebyl-mbromoaniline
N.N-Dirnechyl-p-fluoro
aniline
N.N-Dimethyl-p-chloroanilin
N,N-Dimethyl-piode
aniline
C,
C,,
75
24U'
232/740
436
54
241U
119/8. 135Pi
436
45
24'"
56
4%
436
59
80
70
72
48
4'"
~ 4
24U'
4-l
436
91
~
4%
95
24-'
436
95
~
462
75
~4~~
C,
(33.5)
' (35.5)
2361740, (33)
(81)
C,
4
~
' 221/740, 164Pi
l-Amino-4-pentam1
>Methyl-Eamino- 1htanol
>Amino-f methyl- 1butanol (wlinol)
>Me&yl-f amino->
butanol
~Methylamino->me&yl>propan01
~Isopmpylaminoethanol
250/740
4
~
' 253/740. (46)
(129)
Compound
Method
(%)
Chapterref. B.p./mm.,
nD.
t (M.P.), Derir.
2-Dimethylaminelpropanol
f Dimethylamino- 1propaaol
1-Dimethylamino-2
propanol
>Amino-i-ethyl-1.3
propanediol
'
Aliphrrtic Hydcoxy Amines
EAmino-l-propanol
l-Amino-Phydroxypropane
3- H ~ d r o w p r o ~ ~ l a r n i n e
>Amino- 1.3 propanediol
>(N-Methy1amino)- 1ethanol
Dime&ylaminomethanoI
C,
>Amino- l-butanol
l-Amino->butan01 ( a s
oxdate)
f Ami no- >butan01
>Amino-Emethyl- 1propm01
4-Aminel-pmtanol
?Amino- l-pentmol
f Amino-i-pmtanol
N,N-Diethyl-o-chlorw
aniline
N,N-Diethyl-mchloroaniline
N,N-Diethyl-p-chloroaniline
3,3'-~ibromobenzidene
TABLE 8 6 IfYDROXY AMINES
C,
l-Amino->methyl-2
propanol
p- Ethyl aminoethanol
>Amino-1,f tutanediol
>Amino->methyl- 1,f
propanediol
(35)
For explanations and symbols s e e pp. xi-xii.
c,
(S.)
84
80
5"
425
434
442
74
95
25
24"
2424-'
452
84
84
85
80
63
24=
....
70
24"'
1.4050
173.
80/11
(ZOOd), 113Bz
5 l'
5"
425
90
24'
434
425
100
83
2424"'
435
84
425
49
80
90
24&'
5"
24'
Chapterref. B.p./mm.,
ntD. (MP.), Duiv.
Aliphatic Hydcoxy Amines (continued)
436
~
Method "'ld
Compound
Aromatic Halo Amines (continued)
C8
699
T A B L E 86. HYDROXY AMINES
80/18. 1.4502. 114Pi
78/15
73/ 11
65/4. 158/738
186
116/1, 1.4891, 97HU
56/11, 1.4385, 148Pi
162/742, 1.4482
69/10, 1.4486, iU5HU
C,
>Amino-l-hexaaol
2 H y h x y - f aminohexme
>Amino-4-methyl-lpentanol
4-Methyl-4-amino->
pmmol
~~eth~lamino-l-pentanol
2,pDimethyl-f methylamino- l-propaaol
l-Isopropylamino-ipropanol
fEthylamino->me&yl-2
propanol
f Dimethylamino-l-bum01
.442
30
24&
145155
4%
442
84
425
35
55
80
96
2424-'
5 l'
24'
169, 1.4440
16f)
113/2, 1.4833"
426
431
452
425
436
425
80
77
60
92
32
86
24'"
24"
2424"
~ 4
24"
119/25, lOOBz
81/1, (39)
271
100/10, 1.4419
'81/1, 1.4551"
98/10,1.4468
84
~
5"
(119)
117Hd
91
6(,
5*'
4%
52
~4~
143. 1.4338. 138Pi
431
442
4%
95
76
82
24=
24"
24"
87/23
171
65/37
443
65
24"'
113/150
442
70
24-
126/758
425
92
24'
84
97
84
434
79
65
45
55
30
34
5*
5"'
5
~4~
104/13, 114Pi
95/20, 207Db
95/11, (44), 1 6 3 H a
99/11
75/ 15
431
79
436
431
50t
72
57
97
245,"
24=
24=
97/3
70-82/12
71/14, (46). 1 7 3 ~ C 1
76/22. 1.4322a5, 131Pi
436
56
~
79
35
For explanations and symbols see pp. xi-xii.
1"
4
5'"
'
~153. 1.4344. 133Pi
7~ 14, ~ O S B Z H C ~
l
700
T A B L E 86. HYDROXY AMINES
Ch. 24
AMINES
TABLE 86 (c~ntinued)
TABLE 86 (continued)
c,
Compound
Mehod y(i2:d
. .
chapterwf- B.p./mm..
c,
n b . (M.p.b Deriv.
C,
C8
Cp
C
,
4Dimerhylamincr2butanol
f Dimethylamincr2methyll-pmpanol
fDimethylamino->methylIpropanol
P-Dierfiylaminoethanol
>Amino-2,4dimethyl-lpentanol
1-Ethylamincrtpentanol
5.Dimethylamino- 1pentanol
4.Dimethylamino->methyl2 butanol
2Diethylamino- l-propanol
f Di ethylamincr l-propanol
2,EDimethy l- f dimethylamino- l-propanol '
l-Diethylamincr2propanol
5.Isopropylamino- lpen tanol
~Dimethylamino-Emethyl2pentanol
f Diethylamincr l-butanol
4Diethylamincr 1-butanol
l-Diethylamincr f butanol
5.Diethylaminw l-pentanol
2-Diethylamino- f methyl1- butanol
2,2Dimethyl-f diethylamino- l-propanol
1-Diethylamino->-hexan01
5~7a
5"
79
84
85
50
tram- IAminocydcr
pentanol
C6 2Aminocyclohexanol
cis2Aminocyclohexanol
ems-2-Aminocydohexanol
ds2Aminocyclohexanol
t r m s ~Aminocydohexanol
436
40 t
24'"
130/743, 1.4215, ll5HCl
436
442
70
81
24=
24-'
65/18, 1.4389"
160/741, 1.4389"
84
80
5"
436
431
32
59t
24U'
24'%
81/1.0, 1.45511',
114/23
436
34t
24'"
160/743, 1.4295, 141HCI
84
436
436
63
91
64
5"
24'"
24m
66/18, 1.4332
95/28
63/ 15, 132HC1
442
88
24m
63/22, 1.4265..
431
71t
24U0
98tia
436
34f
24'"
99/30, 1.4400, 154HCI
79
84
79
436
45
52
40
E0
5~8s
506
516'
24'-
85/13, l6lBzHCl
92/9. 1.4474
73/20, ll6HCl
82/18, 1.4372". 116HC1
95
84
68
44
5
5"
131/23, 1.4544
90/14
79
86
5
88/12
80
88
5"'
108/10, 1.4490"
24-
194HCI
442
447
63
68
24"'
24'"
214, (66)
110/15, (70), 185HC1
108/15, (67), 175HU
24"
24"
24w
l- Aminomethylcyclohexanol
2-Aminomethylcyclohexanol
l-Amino- l-hydroxymethylcyclohexane
( %)
~ h a p t e f l e ~B.p./mm..
.
C O 2(N-Cydohexylamino> lerhanol
C Q 2-Amino-2cyclohexyl- 1propanol
2Amincrf cyclohexyl- 1propanol
139HClm
40
50
72
64
C,
148HBr
442
435
43'5
442
ds-frm-4Aminocyclohexanol
1- Amino- l-hydroxymethylcyclopen tane
l-Aminomethyl cydopentanol
98/12, 1.4563
Aromatic Hydroxy Amines
-
I
!
I
1
Method
C,
164
Alicyclic Hydroxy Amines
C,
COmpound
Alicyclic liydroxy Amines (continued)
Aliphatic I$drory Amines (continued)
C,
70 1
(73)- 187HC1
104/7, (66). 175MC1
l l l / l h , (69), 16902
C 6 o-Aminophenol
mAminopheno1
C, o-Aminobenzyl almhol
mAminobazyl alcohol
446
438
84
425
72
50
78
100
C,
427
442
84
80
18
93
24"'
245
425
88
24,'
425
94
24m
425
426
84
87
71t
52
24"
24'=
5 O'
79
70
5m
79
90
5
436
450
69
80
/?-Amino-a-phenylethyl
alcohol
&Amino-pphenylethyl
alcohol
p(rtAminophenyl>
ethanol
mAminophenylmethy1-
C Q >Amino- l-phenyl- lpropanol
2-Amino- f phenyl-1propanol
fAmino-l-phenyl-l*propanol
a-Phenyl-&methylaminoethanol
fAniline l-propanol
For explanations and symbols s e e pp. xi-xii.
24=
241W
5"
24,'
"'
24lS9
24&'
n b . (M.P.), Dcriv.
702
T A B L E 87. AMINO E T H E R S
Ch. 24
AMINES
TABLE 8 6 (continued)
c,
Compound
Merhod '"ld
(%)
TABLE 87 (continued)
Chapteflef. B.p./mm.,
n b , (M.P.), Deriv.
c,
Compound
79
C,
C
l-Amino- Ephenyl-Ebutanol
EAmino-f phenyl-pbutanol
Ehkthylaminel-phenyl- 1propanol
P Erhylaminw a-phenylethyl alcohol
&Amino- l-naphthol
l-Amino-Enaphthol
,, EAminwj-phenyl-3pentanol
1-Phenyl-Emethylaminw
l-bulanol
EMerhylaminwf phenylf bu tan01
5-Aniline l-pentanol
2-Dierhylaminomethylphenol
C,,
Phenyl-ydimethylaminopropylcarbinol
/-Diethylaminwa-phenylethyl alcohol
6-Anilino- l-hexanol
5'
57B1
...
96
65
1.5775"
125/1, 1.5727"
89
89
431
79
442
73
63
81
90
56
~4~
433
433
75
85
24'"
24'"
89
93
5a
222HC1
79
79
89
GO
90
75
5
5 167
5a
202HC1, 168Pi
(90)
235HC1
436
444
45
69
~4~~
~ 4
5a
5a
24"
18 lHC1
239HC1
115-120/5
(77)
14+164/14,
167
~
C,
(78)
C9
C,,
C,,
16411.4
'67/2, 1.5108"
C,
5a
436
66
~4~
145/14, 1.5101"
436
74
241e7
138/0.05, (42)
Merhod
427
427
428
427
C,
435
436
GO
79
24'"
~4~
69/13, 1.4271
84/15
l-Erhylaminw Gmethoxyherane
l-Methoxy-4-ethylaminohexane
l-DimethylaminwG
methoxyhexane
436
73
24'"
90/2, 1.4269'~
436
GO
24''
89/16
436
78
2417'
78/11
1-Dierhylaminw5-merhoxypentane
/,,R',/"-~riethoxytriethdamine
436
91
24"'
77/18, 1.2490
115
66
6
P Erhoxy-~hexylamine
Aromatic Amino Ethers
107/0.07, (48)
C,
( %)
c h a p r n m f . B.p./mm.,
50
50
42
59
24'"
24"'
24'24'-
P
-
m-Aminoanisole (manisidine)
/-Phenoxy ethylamine
p- Aminophenetole
3,&Dimethoxyaniline
(4- aminoveratrole)
C9 y-Phenoxypropyl amine
EPhenoxyisopropylamine
N-Ethyl-p-anisiane
p-Methoxydimethylaminw
benzene
n b , (M.P.), Detiv.
C,,
6-Phenoxy-n-butylamine
Phenoxypropylmethylamine
PEthoxy-Pphenylethyl
amine
f
Aliphatic Amino Ethers
C6 P E t h o x y - ~ b u t y lamine
Diethylaminomethyl
methyl ether
Di-(y-aminopropyl) ether
~ 4
24'*
-
?
1.4220
~ 56/15,
'
134/756
44
69
l-MerhylaminwGmethoxyhexane
TABLE 87. AMINO ETHERS
Compound
chapterref. B.p./mm., n b . @LP.), Deriv.
435
445
C 7 PErhoxy-n-amyl amine
Dierhylaminomethyl ethyl
For explanations and symbols s e e pp. xi-xii.
c,
(K)
Aliphatic Amino Ethers (continued)
Aromatic Hydroxy Amines (continued)
C 9 p-Dimethylaminobenzyl
alcohol
Method
C,,
f Phen~xy~ropylethylarnine
j-Phenoxypropyldimethylamin e
p-Methoxydiethylaminw
benzene
C,,
EAminodiphenyl ether
2-Merhoxy-f aminohexme
For explanations and symbols see pp. xi-xii.
137/12, 195HC.l
704
Ch. 24
AMINES
T A B L E 89. AMINO K E T O N E S
TABLE 8 7 (continued)
c,
Compound
Method
( %)
TABLE 89. AMlNO KETONES
a a p t e s e f . B.p./mm-, n h , (M.p.), Deriv.
Aromatic Amino E th ers (continue4
Cl,
C,,
C,,
115
57
614
191/14. (37)
4-Aminodiphenyl ether
425
115
84
65
2464
614
148/1, 141HC1
(83.5)
425
100
24=
l89/l4. (83.5)
436
94
24'"
150/20, 1.4987, 102tlU
436
90
24'14
148/3. 1.5010, 135HC1
For explanations and symbols s e e p p . xi-xii.
TABLE 88. AhiINO ALDEHYDES
cn
C,
C,
Compound
Method
Yield
(%) chapterref. B.p./mm.,
a-Dimethylaminoisobutyraldehyde
a,a-Dimethyl-pdimethylaminopropional dehyde
o-Aminobenzaldehyde
nr-Aminobenzaldehyde
p-Aminobenzaldehyde
24''
(%)
Chapterref.
B.p./mm.,
n h . (M.P.). Deriv.
Aliphatic and Alicyclic Amino Ketones
f Aminodiphenyl ether
f Phenoxypropyldiethylamine
l-Phenoxy-Gethylaminohexane
Method
Compound
C,
426
426
436
444
96
83
74
45
24"'
24'"
24"'
24U'
75HC1
443
70
2404
(127)
C, Diethylaminoacetone
C O l-Diethylamino-f
butanone
Diacetonethylamine
436
444
72
59
24'"
2441'
70/32, 1.4249, 143Se
70/11, 1.4333'~
443
42
24416
191
Cp
184
46
10-
83/11
4%
79
24*'
91/24, 104Se
436
443
444
55
37
71
24'24"'
24410
184
42
10'"
95/16, 1.4337''
184
44t
10'~
108/20
184
60'
10'~
98/11, 1.4380''
444
85
2441'
103/13
C,
C,
n b , (M.P.), Deriv.
129
C,,
C O m-Dimethylaminobenr
aldehyde
P-Dimethylaminobenzaldehyde
Aminoacetone
Diaminoacetone
Dimethylaminoacetone
l-Dimethylamino-3butanone
Di ace tonamine
( a s acid oxalate)
l-Dimethylamino-f
methyl- Fhexanone
l-Diethylamino-2pentanone
l-Diethylamino- f
pentanone
2-Dimethylaminomethylcyclohexanone
FDiethylamino-2hexanone
l-Diethylamino-4
hexanone
l-Diethylamino-F
hexanone
2-Diethylaminomethylcyclopentanone
36/25. 1.4128, 137SeD
70/40, 1.4213''
.
84/13, 1.4368''
56/36, 102Se
97/11.5, 146HU
Aromatic Amino Ketones
C
p-Formylphenyl-trimethylammonium iodide
C,, mDiethylaminobenzaldehyde
p-Diethylaminobenzaldehyde
For explanations and symbols s e e pp. xi-xii.
CO ~Aminoacetophenone
hydrochloride
o-hinoacetophenone
m-hinoacetophenone
p-Acetylandine
N.N-Dimethyl-Pbrormaniline
437
75
24"'
(187)
425
425
178
431
78
71
88
24,'
24"
10"
24"'
113/6, 75Ac
(99), 128Ac
168/6, (106), 166Ac
145/22, (53)
C9
426
452
425
425
88
80
76
96
24"'
2424''
24"
114HC1
127HC1
1 6 / 1 7 , 74Ac
169/15, (42), 93Ac
436
80
24"'
121/4, (52)
a-Aminopropiophenone
/?-Aminopropiophenone
o- Aminopropiophenone
m~minopropiophenone
CI0 2-Phenylamino-f butanone
19
For explanations and symbols see pp. xi-xii.
AMINES
TABLE 90 (continued
TABLE 8 9 (continued
1
c,
Compound
Method Yield Chapterref- B.p./mm.,
n h , (M.P.), Deriv.
(%)
Aromatic Amino Ketones (mntinued)
Clo a-Methylaminopropiophenone
o-Dimethylaminoacetophenone
Cl, 3Phenylamino-2pentanone
a-Methylaminoburyrophenone
l-Phenyl-f dimethylamino-lpropanone
P-Dimethylamin~~ropiophenone
C,,
C
l-Dimethylaminet
phenyl-lbutanone
PDimethylamineamerhylpmpiophenone
,,
1Aminobenzophenone
44'-~iaminobenzophenone
1-Amino fluorenone
4-Aminofluorenone
C,,
l-Phenyl- l-phenylaminopropanone
C16 P-Dhethylaminobenzil
c,
C,
436
57
24'-
177HCl
436
56
24'-
94A.5, 184F'i
436
72
24m
120/1
436
70
24'-
194IIU
187
53
10676
141/2G, 127Pi
444
72
24U0
156HU
436
43
24'"
107/3.5, 1.5070
444
74
24a
82/1, 1 . 5 1 ~ 2 ~ ' ,154HCI
446
183
446
446
92
70 t
56
74
24lS9
10le
2416'
2416'
(107)
(245), 241Ph
(118.5), 138Ac
436
74
24"'
(91.5)
179
90
10'~~
(1 16)
C,
C,
Aminoacetic a c i d
(glycine)
Method
Yield
(so)
(1 39)
chapterref. B.p./mm.,
C S a-Aminopropionic acid
(alanine)
92
87
77
54t
85t
72f
60
13'19
13'"
241M
24"'
24*U
13,19
13'~
n b , (Map.), Deriv.
PAminopropionic acid
(palmine)
253
435
451
247
247
44t
70
71
90
86
13'"
24lW
24=
1313,"
(263), 6 7 h *
(246), 62An*
(2364
a-Amino-n-buryric acid
a-Methyl-P-alanine
N-Methylalanine
N-Ethyldycine
N,N-Dimethylglycine
a- Aminosuccinic (maspartic) acid
a,y-Diaminoburydc acid
meso- a , p D i a m i n e
succinic acid
a-AmineP-hydroxyburyric acid
C,
247
247
435
447
452
247
247
PAminopropionic acid
( p a l a n h e ) (cot3 inued)
y-Aminoburyric acid
a-hminoisobutyric acid
TABLE 90. AMINO ACIDS
Compound
Compound
a-Aminephydroxypre
pionic acid (serine)
For explanations and symbols s e e pp. d-xii.
c,
707
T A B L E 90. AMINO ACIDS
Ch. 2 4
Method
(5%)
n k , (Up.), Deriv.
247
247
247
248
249
427
437
446
97
247
90
75t
69t
70
72
75
85
45
40t
51t
13"a
13'"
13"'
13'01
13'~
24'%
24lS9
24'"
5'"
13'"
(198)
(200)
(197)
247
253
278
431
435
447
452
247
247
247
253
280
427
451
451
431
278
451
449
434
6lt
50t
82
58
13"~
13"~
13'~
24"'
24'"
241W
24u'
13'"
13'"
13'19
13'"
13=
24'"
24"9
24'P9
24='
13OU
24"'
242dW
(304), 75hm*
140Dz
142Dz
60
2lt
62
70
33
731
771
76
73
81
70
100
43
95
41
90
a-hminovaleric acid
(norvaline)
y-Aminovaleric a c i d
6-Aminovaleric acid
(295), 62Am*
(295)
163Bz
(2954
Chapterref. B.p./mm.,
a-Aminoisovaleric acid
(d-valine)
(198), 123HC1*
add
For explanations and symbols s e e pp. xi-xii.
(195)
(195)
(2004
(198d)
(244), l5OBz
182HC1
198Bz
127h*
(182)
(317d). 129Dz
(182d)
(183)
162Bz
(280d)
(215d), 181Pi
(3064
1
708
Ch. 24
AMINES
l
TABLE 90 (continued)
GJ
C,
Compound
d-a-Methylminobutyric
acid
7-N-Methylaminobucyric
acid
N-Methyl-a-aminoisobutyric
acid
N,N-Dimethylalanine
monohydrate
a- Aminoglutaric ( d glutamic) acid
a-Amincra-methylsuccinic acid
a, F-Diamino-~valeric
acid (d-ornithine)
Methyliminodiacetic acid
7-Methylmercaptcra-amincr
butyric acid ( d methionine)
C,
Method
431
(%)
62
c h a p t e 6 e f . d.p./mm.,
24-'
I
n b . (M.P.). Deriv.
TABLE 90 (continued)
c,
a- Amino-a-ethylbutyric
acid
a-Dimethylminoi scr
butyric acid
a-Aminoadipic acid
a,F-Diaminoadipic acid
a.c-Diaminocaproic acid
(d-lysine)
d - l y s i n e dihydmchloride
1-Cy stine
Method
I
(%l c h a p t e r r e f B.p./mm.. n D
. (M.P.). Deriv.
C 6 Histidine
I-Histidine hydrochloride
dArginine hydrochloride
278
....
....
....
CT a- Aminoheptanoic acid
7-Aminoheptanoic acid
P,PDiethyl-,E-amincr
propionic acid
N,N-Dimethyl-d-valine
a-Methyl-y-dimethylaminobutyric acid
P-Dimethylaminopivalic
acid
p 2-Thienylalanine
C,
45
90
13'~'
1313'"
(272)
(252)
(220)
278
427
443
55
30
30
13'~
243'7
24a6
(281). 13592
(187)
(184)
431
249
100
24"'
13'~
( 152), 164tiCI
90
253
74
1
426
68
24'14
(275)
55
92
40t
13=
13"'
13'"
(273), 128132
a- Amincra-phenyl-
278
280
247
(267)
propionic acid
a- Amino-Pphenylpropionic acid
278
278
83
67
13'"
13'~
146Ac
(257),
431
435
447
447
446
62
621
50
441
264
264
443
260
50
70
34
481
3
(76)
~
(99)
a - ~ m i n & c t a n o i c acid
N,N-Dimethyl-d-leucine
a- Aminophmylacetic
acid
o:Aminophenylacetic acid
m- Aminophenylacetic acid
p- Aminophenylacetic acid
d-a-Aminwz-caproic acid
(norleucine)
7-Aminen-caproic acid
E-Aminocapmic acid
d-a- Amino-pmethylvaleric acid
a- Aminoisocaproic acid
(1 eucin e)
Compound
p-Aminomethy1)benzoic
acid
Cp
a-Aminononanoic acid
d-a-Amino-,E-phenylpropionic acid
PAmincra-phenylpropionic acid
PAmino-pphenylpropionic acid
p- @- Aminoethyl)
b m z o i c acid
m-Dimethylaminobenzoic
acid
p-Dimethylaminobmzoic
acid
'
66
431
100
431
263
80
50
For explanations and symbols s e e ppr xi-xii.
710
AMINES
Ch. 24
TABLE 90 (mnlinud)
TABLE 91 (continued)
p
p
-
Compound
249
65
13"
Cm d-y-Phenyl-a-amine
butyric acid
c11 T W P W P ~ ~ ~ ~
431
62
24-
278
278
45t
88
1313='
---
Method
(9;)
_.
(282). 206Ac
193Bz
~ h a ~ t c r r eB.p./mm.,
~.
nb, (M.p.), Deriv.
C,
Methyl a-aminoiaobutyrate
Ethyl a-aminopmpionate
Ethyl /3-aminopmpionate
Methyl pmethylaminopropionate
C, Ethyl p a m i n m b u t y t a t e
Ethyl pmethylamine
propionate
C7
C,
Ethyl /3-arnho-wvderate
Ethyl a-methylasnine
butyrate
Ethyl ,&methylaminenbutyrav
Ethyl aminomalonate ( a s
acetyl derivaave)
Ethyl a-aminmcaproate
Ethyl pamin-caproate
Isobutyl a-aminoise
butyrate
Ethyl pethylaminenburyraw
Methyl pdiethylamine
propionace
Ethyl a-eminosuccinate
(dl-asparac e stet)
.
14"
1417'
51/12
143Ha
134, 183HC1
40
14~'
14'
24'a
24M
24M
56/ 10
67Ha
50/ 11
426
443
443
21 t
55
49
24'"
24a
24,"
69/17, 148Pi
62/10. 74Am
68/18. 1.4218~'
426
436
23t
63
24&'
24-
84/17
65/20, 1.4174, 104Pi
443
89
24a
66/10
426
44t
24'-
(90 .
426
426
285
86
48
66
24"
24s'
14"
88/11
104/25
6 Y 4 1.4210, l03HU
431
68
24s'
75/12
285
285
427
434
443
443
67
90
64
95
74
100
LOO
24+"
-.
70
24%
-.
__p--.
..
. .-.
__
.._.__.
-
.
-
285
63'
14'-
83/16
436
74
24"'
63/3, lO2HCl
436
84
24'"
75/13
436
74
24"'
117/15, 1.4320''
285
70t
14"'
105/17, 1.4342
.
.
.
p
.
C,,
~
-
----~----p
Methyl p-aminobcnwate
,
propionate
Ethyl p a m i n e p p h e n y l propionate
For explanations and symbols see pp. xi-xii.
TABLE 92. AMINO CYANIDES
Chaptermf. B.p./mm.,
Compound
c,
. -.-
-- - -
- ---
-
(7.)
-- - -
--
..-
Aminoacetonitrile hydre
chloride
Aminoacetonitrile hydrogen
sulfate
391
95
X)'"
....
81
24'"
For explanations and symbols see pp. xi-xii.
t
nD
, (Mg.), Dedv.
-
----
..
-_--
Alipharic and Nicyclic Amino Cyanides
66.5/8
98/ 1
Methyl o-aminobenzoate
Methyl m-amino benzoate
C p E h y l p-aminobenzoate
Ethyl a-aminophenylC
acetate
Ethyl m-aminophenylacetate
Ethyl p-(aminomethyl)
bcnzoate
Methyl Panilinopropionate
Methyl o-dimethylamin@
benzoa te
C,
426
-
Aromaac Amino Esters
-
292
293
-_
_
.. _
__-_.
-___.----p.
Ethyl a-methyl-ydimethylaminobutyrate
Methyl y-diethylamin@
tutyrate
Ethyl a-diethylamin@
propionate
Diethyl dimethylamine
malonate
C,, Ethyl y-diethylamin@
butyrate
.
p
Methylpaminopropionate
Ethyl aminoacemte
. .-
Yield
Chapter'ef. B.p./mm.. ntD, (MP.), Deriv.
Method (7.)
C'
ALiphatic Amino Esters
C,
.-..
Aliphaac Amino Esters (currtinued)
TABLE 9 l. AMINO ESTERS
Compound
.
Compound
__________
(60)
For explanations and symbols s e e pp. xi-rii.
c,
-
C
C9 p-Anilinopropionic acid
71 1
T A B L E 92. AMINO CYANIDES
(166)
712
Ch. 24
AMINES
TABLE 92 (continued)
-
C,
Compound
Method
(%)
chapterref. B.p./mm.,
n L , (M.p.). Deriv.
C,
C,
,E-Aminopropionitrile
Methylaminoacetonitrile
Methyleneaminoacem
nitrile
388
391
391
33
93
71
20'"
203"
203"
65/20
(129)
3Aminen-propyl cyanide
452
391
jsf
77
2420"'
97/20. 1 4 0 H a
48/11
391
388
80
78
203"
20"
68/24, 1.4198
74/16, 1 . 4 3 4 2 ~
391
391
392
70
83
100
20"~
20'~
2oSU
83/29
134- 137, 1 . 4 0 9 5 ~ ~
(75)
391
57
203"
54/18, 133/747, 1.4176
388
391
30
89
2oaS0
20'"
203*
95/30, 1.4322
169HC1
85/20
118/14, 98Bz
71/11
85/25
74/14, 167, t436214, 1 0 3 ~ i
70/2O
a- Aminoisotutyronitrile
P-Methylaminopropioninile
Ethylaminoacetoniuile
Dimethylaminoacetoniuile
Iminodiacetonitrile
C,
C6
a-Methylaminoisobutyroninile
PEfhylaminopropioni trile
Isopropylaminoacetonitrile
5-hino-n-amyl cyanide
a-Aminodiethylacete
niaile
a-Methyladno-nvaletonitrile
a-Methylaminoiscr
valeronitrile
a-Methylamino-a-methyln-butyronitrile
391
30
452
391
68f
40
24"
203"
391
392
391
85
77
80
203*
20"'
203g0
391
83
2
P-n-Pro~ylamino~ropie
388
niuile
P - I s ~ p r o p y l a m i n o ~ r o ~ i e 388
niuile
a-Dimethylaminobutyre
391
nitrile
4-Dimethylaminobutyre
387
niaile
a-Dimethylaminoisobutyro- 391
nitrile
391
391
Diethylaminoacetwiuile
C,
a-Aminomefhylbutylacete
nitrile
a-Aminomethylisobutylacc
toniuile
0
89/20, 1.3496
~ 68/17,
~ ~ 1.4282".
92
20'~
121/K), 1.4362
95
20U'
87/17, 1.4230U
78
2o3I9
68/23
64
20"'
44-47/1.5
C7
69
20"~
57/25
m
203"
2tj312
50/2O, 1.4215
63/14. 1.4230"
391
51
20317
391
53
2o3l7
a-Methylaminea-ethylbutyronitrile
a-Dimethylamino-a-methylbutyroninile
a-Mefhylethylaminoisobutyronitrile
a-Diethylaminopmpie
nitrile
,E-Diethylaminopropicnitrile
l-Aminel-cy a n o c y d e
hexane hydrochloride
acetoni mile
a-Dimethylaminea-methyl-
isovaleronitrile
a-Dimerhylaminea-ethylbutymnivile
7-Diefhylaminobutyre
niuile
a-Diethylaminoisobutyre
niuile
chapterref. B.p./mm., n L , (M.P.), Deriv.
391
73
203"
167/765
391
70
203"
63/12
391
53
2O3I9
58/14
391
391
388
436
65
68
97
56
77
203=
203"
20'~
24194
203~
49/7,68/17
55/11
120/70. 1.4353
84/13, 1.4343"
(204)
391
49
2OsU
7 5/ 10
391
75
20 319
69-73/10
378
387
436
391
391
84
83
97
59
39
2oU3
20aU
24"'
203"
2o3l9
93/14
89/9
103/21, 1.4351, 70Pi
68/14, 1.4312
74/14
391
39
203"
@/4
388
92
20aa
124/4, 1.4764
436
391
90
92
2419,
102/4,62Pi
2 0 ~ ' ~ 89/11
83Bz
valeronitril e
a-Diethyl aminoise
valeroniuile
,E-Cyclohexylamine
propionitrile
C,
88
(9%)
Aliphatic and Alicyclic Amino Cyanides (continued)
Aliphatic and Alicydic Amino Cyanides (continued)
C,
..-,
Compound
a-Dierhylaminocaprmiuile
a-Diethylaminea-isotutylacetoninil e
Aromatic Amino Cyanides
88/ 10
C, m-Aminobenzoniuile
C B c-Aminobenzyl cyanide
p-Aminobenzyl cyanide
Anilinoacetonitril e
425
425
425
391
63
88
79
35
24"
24'"
24"
20~'~
(53). 131Ac
(72)
147/1
(4 7)
C 9 Methylphenylaminoacem
niuile
391
76
203"
14V9
76/ 10
For explanations and symbols s e e pp. xi-xii.
7 14
AMINES
l
Ch. 24
REFERENCES FOR CHAPTER 24
REFERENCES FOR CHAPTER 24
c,
Compound
Method
Yield
chapterref' B.p./mm.,
'Senkus, Ind. Eng. Chem, 40, 506 (1948); cf. ref. 54.
ntD, (M.P.), Deriv.
' Johnson and Degering, J. Am. Chem Soc., 61, 3194 (1939); Hass and Riley,
Chem Revs., 32, 389 (1943).
'Clemo and Ormston, J. Chem Soc., 1778 (1932).
Aromatic Amino Cyanides (cvntinued)
C m PBenzylaminopr~~ie
nitrile
a-Dimethylamin~phen~lacetoniuile
388
73
20'"
185/23
391
29
20'~
90/6
C ,a a-Diethylaminophenylacetoniuile
391
391
83
56
20'~
20"
11217. 131/11
124/9
,, a- Aminodiphenylaceto-
392
77
20"'
(102)
386
74
201W
12211
392
X)
20'~
(36)
C
nitrile
y-Dierhylamino-a-phenylbu tyron i tril e
9Aminepcyanofluorene
For explanations and symbols see pp. xi-xii.
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"
I
"
"
"
"
f
716
AMINES
Ch. 24
U Mahood and Schaffner, Org. Syntheses, Coll. V o l . 11, 160 (1943).
*Morgan and Walls, I. Soc. C h e m Ind., (London), 50, 94T (1931).
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"
"
"
.
REFERENCES F O R C H A P T E R 2 4
717
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'
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718
AMlNES
Ch. 24
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,
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720
1
AMINES
REFERENCES FOR CHAPTER 24
Ch. 24
I
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'"Graebe and Rostovzeff, Ber.. 35, 2747 (1902).
'67Hunuess, Pfister, and Pfister, J . Am. Chem. Soc., 64, 2845 (1942).
"OClarke and Behr, Org. Syntheses, Coll. Vol. 11, 19 (1943).
'69Natarajan and Swaminathan, J . Am Chem. Soc., 69, 2560 (1947).
"OSmith in Organic Reactions, Vol. 3, John Wiley & Sons, New York, 1946,
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"'Buchman e t al., J . Am. Chem Soc., 64, 2696 (1942).
a74McCoubreya n d Mathieson, J . Chem. Soc., 696 (1949).
'"Kenyon and Young, J . Chem Soc., 263 (1941).
'"Mayer and Sieglitz, Ber., 55, 1847 (1922).
a7'Goldberg, Ordas, and Carsch, J . Am. C h e m Soc., 69, 260 (1947).
a78Smith, ref. 270, p. 381.
'"Skits and Rzssler, Ber., 72, 461 (1939).
"ONaegeli a n d Lendorff, Helv. Chim. A c t a 15, 49 (1932).
'"Stevenson and Johnson, J . A m C h e m Soc., 59, 2525 (1937).
'"Singleton and Edwards, J . Am. Chem Soc., 60, 540 (1938).
'"Mayer a n d Krieger, Ber., 55, 1659 (1922).
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'%agnon, Gaudry, and King, J . C h e m Soc., 13 (1944).
a89Curtius, J. prakt. C h e m , 125, 211 (1930).
a90Curtius and Sieber, Ber., 55, 1543 (1922).
19'Yale, Chem. Revs., 33, 209 (1943).
'9'Wolff in Organic Reactions, Vol. 3, John Wiley & Sons, New York, 1946,
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'9'Adamson and Kenner, J. Chem. Soc., 842 (1934).
a940esterlin, Z.angew. C h e m , 45, 536 (1932).
'95Briggs and Lyttleton, J . Chem. Soc., 421 (1943).
'96v. Braun and Friehmelt, Ber., 66, 684 (1933).
"'Benson, Hartzel, and Savell, J. Am. C h e m SOC., 71, 1 1 1 1 (1949).
'98Dice a n d Smith, J. Org. Chem, 14, 179 (1949).
'99Fuson, Maynert, and Shenk, J. Am. C k m Soc., 67, 1939 (1945).
'ODAdamson, J. Chem Soc.. 1501 (1939).
'OISchmidt, Ber., 57, 704 (1924).
'OaNystrorn and Brown, J . Am. C b e m Soc., 70, 3738 (1948).
'O'Adams and Marvel, J. Am C h e m Soc., 42, 314 (1920);Suter and Moffett,
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'04Bloom, Breslow, and Hauser, J . A m Chem. Soc., 67, 539 (1945).
'05Walter and McElvain, J . A m C h e m Soc., 56, 1614 (1934).
'WSuida and Drahowzal, Ber., 75, 995 (1942).
'07Carothers and Adams, J . A m C h e m Soc., 47, 3051 (1925).
'08Adkins and Billica, J . Am. C h e m Soc., 70, 695 (1948).
'"Adkins and G a m e r , J . A m Chem. Soc., 52, 4349 (1930).
"ORobinson and Snyder, Org. Syntheses, 23, 71 (1943),footnote 5.
"'Freeman, R h & , and Spoeni, J . Am. C h e m Soc., 69, 858 (1947).
"'Geissman and T e s s , J . Am. Chem Soc., 62, 514 (1940);St. Goldschmidt
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"'van d e Kamp, Burger, and Mosettig, J . A m C h e m Soc., 60, 1321 (1938).
"4Crowe a n d Nord, 1. Org. Chem, 15, 81 (1950).
"5Kolloff and Hunter, J . Am. Chem. Soc., 63, 490 (1941);cf. P r i j s , Lutz, and
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"'Turner, 1. A m Chem Soc., 68, 1607 (1946).
"'King and Acheson, J . Chem Soc., 683 (1946).
'"Reihlen e t al., An=, 493, 20 (1932).
722
AMINES
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''°Corse, Bryant, and Shonle, J. Am. Chem. S a ; , 68, 1905 (1946).
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"4Malachowski e t al., Rer., 71, 759 (1938).
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''OTarbell and Noble, 1. Am. Chem Soc., 72, 2657 (1950).
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"'Kindler and Peschke, A r c h P h a n , 269, 581 (1931).
"4Wiley and Adkins, I. A m Chem Soc., 60, 914 (1938).
"'Mousseron, Jullien, and Winternitz, Bull. soc. c h i m France,. (5) 15, 884
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"'Ruggli and Businget, Helv. Chim Acta, 25, 35 (1942).
"'Schultz, I . A m C h e m Soc., 69, 1056 (1947).
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"'Pollack, I. A m C h e m Soc.. 65, 1335 (1343).
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'UWojcik and Adkins, J , A m C h e m Soc., 56, 2419 (1934).
'"Uffer and Schlirtler, Helv. Chim. Acta, 31, 1397 (1948).
'UGavrilw, Koperina, and Klyuchareva, Bull. soc. c h i m France, (5) 12, 773
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'"Winans and Adkins, J . A m Chem Soc., 55, 2051 (1933).
'"Paul, Bull. scc. c h i m France, (5) 4, 112 1 (1937).
'48King, Barluop, and Walley, J. C h e m Soc., 277 (1945).
"'Hass, Susie, and Heider, J. Org. Chem, 15, 8 (1950).
'IOLycan, Puntambeker, a n d Marvel, Org. Syntheses, Coll. Vol. II, 318 (1943).
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'"Breslow e t al., I. A m C h e m Soc., 66, 1921 (1944).
"'Magidson and Grigacnasky, Ber., 69, 396 (1936).
"4Carmack e t al., J. A m C h e m Soc., 68, 1220 (1946).
'=Hurd and Perletz, J. Am. Chem Soc., 68, 38 (1946).
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"'Mills and Grigor, J. Chem. Soc., 1568 (1934).
"'Fischer, Sturm, a n d Friedrich, A n n , 461, 257 (1928).
"'Koessler and Hanke, I . A m C h e m Soc., 40, 1716 (1918).
'60Barry and Hartung, J. Org. C b e m , 12, 460 (1947).
'61Shivers and Hauser, J. A m Chem Soc., 69, 1264 (1947).
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'UGrlinacher, Helv. Chim. Acta, 6, 458 (1923).
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724
AMINES
Ch. 24
411Hartoughet al., I. ' ~ m C. h e m Soc.. 7 0 , 4013, 401 8 (1948).
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414Jones,Marszak, and Bader, I. Chem Soc., 1578 (1947).
41sGillot and G a m l e y , I. A m Chem. Soc.. 67, 1968 (1945).
4 1 6 M a ~ i c hLesser,
,
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417Wildsand Shunk, 1. Am. C h e m Soc.. 6 5 , 469 (1943); Spaeth, Geissman, and
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41aSkoda, Bull. soc. c h i n France, ( 5 ) 13, 328 (1946).
U9Howton,I. Org. C h e m . 12, 379 (1947); c f . Mannich, Ber., 7 5 , 49 (1942).
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4 ' 4 M a ~ i c hand Ganz, Ber..' 55, 3486 (1922).
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4'9Sheehan and Bolhofer, I. Am. Chem. Soc., 7 2 , 2786 (1950).
4'0Smith and Emerson, &g. Syntheses, 29, 18 (1949).
4''Loevenich, Becker, and Schr"or, I. prakt. C h e m , 127, 254 (1930).
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U4Chambret and J o l y , Bull. SOC. chim. France, ( 5 ) 14, 1023 (1947).
4''Miiller and Feld, Monatsh, 58, 15 (1931).
4 3 6 R ~ g g l Leupin,
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4'9Weizmann and Malkowa, Bull. soc. c h i m France, ( 4 ) 47, 356 (1930).
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U4Birkofer,Ber.. 7 5 , 429 (1942).
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"ORiegel, Gold, and Kubico, I . Am. C h e m Soc., 64, 2221 (1942).
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4"Schmidt e t al., Am., 568, 192 (1950).
REFERENCES FOR C H A P T E R 24
4'6Leffler,&g. Syntheses, Coll. Vol. U, 24 (1943).
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467Lefflerand Adams, I . A m Chem. Soc., 59, 2252 (1937).
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477Morsch,Monatsh., 63, 220 (1934).
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489Snyder,Weaver, and Marshall, 1. A m C h e m Soc., 7 1 , 289 (1949).
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491Bachmann,I. Am. C h e m SOC., 59, 420 (1937).
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7 26
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Ch. 24
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'05~osettigand Krueger, I . Org. Chetn. 3, 317 (1938).
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"Baker, I. Chem Soc., 476 (1937).
'06Ritter and Kalish, I. Am. C k m SOC., 70, 4048 (1948).
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'09Parker and Shive, I. Am. Chem SOC., 69, 63 (1947).
510Bergstrom, Sturz, and Tracy, I. Org. Chem, 11, 239 (1946).
'"Glickman and Cope, I. Am C k m Soc., 67, 1017 (1945); Coffey, Thomson,
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'"Brown and Jones, I. Chem. Soc.. 781 (1946).
"'Stewart and Bradley, I. Am Chem. SOC., 54, 4172 (1932).
'14Alexander and Underhill, I. Am Chem SOC., 71, 4014 (1949).
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"'Gattermann and Wieland, Laboratory Methods o j Organic Chemistry, The
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"'Lambert, Scaife, and WilderSmith, I . Chem. Soc., 1474 (1947).
"9Buckley, Heath, and Rose, I. C h a Soc., 1500 (1947).
"ORousseau and Lindwall, I . Am Chem. Soc.. 72, 3047 (1950).
"'Jones and Wilson, I. Chem. Soc., 550 (1949).
"'Barger and Easson, I. Chem Soc., 2100 (1938).
'"Hiers and Adams, 1. Am. Chem Soc., 49, 1099 (1927); Ber., 59, 162 (1926).
'UAllen and Rell, &g. Syntheses, 22, 19 (1942).
snAnslow and King, Org. Syntheses. Coll. Vol. I, 298 (1941).
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s'4Waalkes e t al., 1. Am. Chem. Soc., 72, 5760 ( 1950).
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'40JJian e t al., I. Am Chem. Soc., 67, 1203 (1945).
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ss'Wilkinson and Finar, 1. Chem. Soc., 759 (1947).
Yak,
s 5 * B r ~ in
~ nOrganic Reactions, Vol. 6, John Wiley & Sons, Ne
p. 469.
sroCampaigne, Budde, and Schaefer, Org. Syntheses, 31, 6 (1951).
s61Schultz, Org. Syntbeses, 31, 45 (1951).
/
729
METHODS 465-468
A successful conversion of pfluorenone t o its ketimine h a s been
described in which anhydrous ammonia is passed through the moltec ketone
a t l65O (66%).'
Invariably, the combination of ammonia and aldehydes forms other
products; these reactions have been reviewed.' Monochloramine (NH2Cl)
reacts readily with substituted bentaldehydes t o form aldchlorimines
( ArCH =NU).''
Imines
CONTENTS
METHOD
PAGE
465. Condensation of Carbonyl Compounds with Amines ..................................
728
466. Cyclization of ,&Amino Alcohols ..................................................................
729
467. Action of Grignard Reagents on Oximes ......................................................
729
468. Action of Grignard Reagents on Nitriles ......................................................
727
469. ,LWminonitriles by Condensation of Nitriles ................................................ 730
470. Ethylene Imino Ketones by the Action of Amines on a,,&Dibromo
Ketones ............................................................................................................ 730
...................................................................................................... 731
................................................................................................................ 732
Table 93. Imines
References
465. Condensation of Carbonyl Compounds with Amines
RCHO
+ R'NH,
+ RCH =NR'
+ H20
Both aliphatic and aromatic aldehydes condense with primary amines,
aliphatic and aromatic, to form N-substituted imines. The purely aliphatic
imines (C, t o C,,) can be obtained in 50-80% yield; however, t h e s e compounds are unstable and should b e used immediately after distillation.'
Side reactions which may occur during their formation have been studied.'
On the other hand, Schiff b a s e s from substituted bentaldehydes and
amines, aliphatic and aromatic, are more stable and have been prepared in
large n ~ m b e r s . " ~ The benzaldehyde entity may carry a halo, hydroiyl,
methoxyl, dialkylamino, or nitro goup.' Usually, an immediate reaction
occurs upon mixing the two reactants either without a solvent or in dilute
alcohol, a s illustrated by the synthesis of benzalaniline, C,H,CH=NC,H,
(87%).'
The formation of Schiff b a s e s by the reaction of ketones with amines
is more difficult. Acetophenone and other aryl alkyl ketones which are
slow t o react under the usual conditions will combine with aromatic amines
a t 160-180° in the presence of a zinc chloride-aniline salt." In another
procedure, 2-acetylthiophene and aniline are condensed in boiling toluene
with the aid of a water separator."
Ketones like acetophenone have been heated with ammonia in the
presence of a dehydrating agent, but the formation of the ketimines is
466, Cyclization of p - ~ m i n oAlcohols
Ethylenimine is conveniently prepared from ethanolamine by heating
the inner salt of the sulfate e s t e r with aqueous alkali (37%)." The
method h a s been applied to other p-amino alcohols to form the C-alkyl
homologs of ethylenimine in which one to three of the four hydrogens may
b e substituted."
The general procedure is illustrated by the synthesis
of 2,2-dimethylethylenimine (51%).13 T h e N-alkyl analogs can be made by
treating the N-alkylethanolamine hydrochlorides with chlorosulfonic acid
followed by the action of b a s e on the intermediate sulfuric acid esters,
a s in the preparation of N-ethylethylenimine (70%).14
Aryl-substituted amino alcohols fail t o undergo t h i s reaction but ins t e a d are dehydrated to vinylamines.
The reactions of ethylenimine have been studied extensively."
467. Action of Grignard Reagents on Oximes
R
AIC
II
-CH,
R
I
2RMgX+
H 0
Ar-C-CH2
I
Ar-C-CH2
\/
\ /
Certain substituted ethylenimines are obtained by the action of aliphatic or aromatic Grignard reagents on aryl alkyl ketoximes with s u b
sequent non-acidic decomposition of the intermediate complex (2060%).~~*~'
468. Action of Grignard Reagents on Nitriles
ArCN
RMEX
A
NH
ArRC =NMgX 3 ArRC =NH
TABLE 93. IMINES
IMINES
The interaction of Grignard reagents and nitriles produces kecimines
which may be hydroly~edto ketones without isolation (method 187).
Many of the alkyl aryl ketimines have been isolated for further study.
For this purpose, the intermediate addition compound i s decomposed by
treatment with anhydrous hydrogen chloride or, preferably, with anhydrous
ammonia."-19 The yields range from 50% to 86%. Often, the ketimines
are non-hydrolytable or hpfrolyted with difficulty, allowing them to be
easily isolated;" others must be isolated and stored under anhydrous
condition^.'^^*^^
469. p ~ m i n o n i t r i l e sby Condensation of Nitrilesaa
470. Ethylene Imino Ketones by the Action of Amines on a$-~ibromo
I
Ketones a 3
73 1
TABLE 93. IMINES
Cn
Compound
Method
%
--
l,2-Butylenimine
trrms-2,f Butylenimine
2,2-Dimethylethylenimine
N-Ethylethylenimine
Propylidenemethylamin e
Ethylidene-ethylamine
Propylidene-ethylamine
Butylidenemethylamine
Burylidene-ethylamine
N-Benzylidenemethylamine
N-Benzylidencetb ylamine
2-Phenyl-2-ethylechylenimine
N-Pheiyl 2-thienyl
methyl ketimine
Diphenylmethane
imine hy&ochloride
Fluorenyllidenimine
N-Benzylideneaniline
(benzalaniline)
-
For explanations and symbols s e e pp. xi-xii.
Chapterref.
B.p./mm.. nb, (Mp.). Deriv.
IMINES
Ch. 25
REFERENCES FOR CHAPTER 25
lTiollais, Bull. SOC. chim. France, (5) 14, 708 (1947); Campbell, Sommers,
and Campbell, 1, A m C h e m Soc., 66, 82 (1944).
'Emerson, Hess, and Uhle, I . A m Chem. Soc., 63, 872 (1941); Paquin, C h e m
Ber.. 82.. 316
- (1949).
. - - ,
'Bigelow and Eatough, Org. Syntheses, Coll. Vol. I, 80 (1941).
4Gomwell, Babson, and Harris, I . A m C k m Soc., 65, 312 (1943); ref. 6.
'Cromwell and Hoeksema, I. A m C h e m Soc., 67, 1658 (1945); Moffett and
Hoehn, ibid. 69, 1792 (1947); Lutz et al., I . Org. Chem., 12, 760 (1947);
Jensen and Bang, Ann., 548, 106 (1941).
6Campbell e t al., I . A m C h e m Soc., 70, 3868 (1948).
'Strain, 1. Am. C h e m Soc., 52, 820 (1930).
'Harris, Harrhan, and Wheeler, I . A m Chem. Soc., 68, 846 (1946).
'Sprung, Chem. R e v s . , 26, 297 (1940).
''Hauser, Gillaspie, and LeMaistre, I . Am. C h e m Soc., 57, 567 (1935).
llAllen, Spangler, and Webster, Org. Syntheses, 30, 38 (1950); Leighton,
Perkins, and Renquist, I . Am C h e m Soc., 69, 1540 (1947); cf. ref. 12.
12Joneset al., I. Org. C h e m , 9, 125, 484 (1344).
13Campbell, Sommers, and Campbell, @g. Syntheses, 27, 12 (1947).
14Elderfield and Hageman, I . Org. C h e m , 14, 622 (1949).
lSCampbell et al., I . Org. C h e m , 8, 103 (1943).
16Campbellet al., I . Org. C h e m , 9, 184 (1944).
"Moureu and Mignonac, Ann. c h i m , (9) 14, 322 (1920).
laPickard and Vaughan, I. A m C h e m Soc., 72, 876, 5017 (1950).
lgCloke, I . Am. C h e m Soc.. 62, 117 (1940).
"Lachman, Org. Syntheses, Coll. Vol. 11, 234 (1941).
llReddelien, Ann., 388, 165 (1912); Ber., 43, 2476 (1910).
"Adkins and Whitman, I . A m C h e m Soc., 64, 150 (1942); Darnow, Kihlcke,
and Bawann, C k m . Bet., 82, 254 (1949).
"Cromwell and Caughlan, I . A m C h e m Soc., 67, 2235 (1945); 69, 258 (1947).
'4Campbell et al., I . Am. Chem. Soc., 70, 3868 (1948).
"Bestian, Ann., 566, 210 (1950).
a6Harrough,I . Am. C h e m Soc., 70, 1282 (1948).
Hydrazines
CONTENTS
PAGE
METHOD
471. Alkylation of Hydrazines .............................................................................. 733
472. Interaction of Amines and Hydroxylamine-0-Sulfonic Acid ...................... 734
473. Reduction of Diazonium Compound s ............................................................ 734
734
474. Reduction of Nitrosoamines .......................................................................
475. Reduction of Azo Compounds .................................................................. 735
476. Action of &ignard Reagents on Diazomethane .......................................... 735
477. Reductive Hydrazination of Carbonyl Compounds ...................................... 735
478. Addition of Grignard Reagents to Dialkyl-alkylidenhydrazones .............. 735
These compounds are prepared in part by methods similar to those for
amines; in addition, specific methods are employed including the reduction of diazonium compounds, reduction of azo compounds, and reduction of nitrosamines leading to sym- or unsym-substituted hydrazines.
471. Alkylation of Hydrazines
High-molecular-weight monoalkylhydrazines (C, and above) can b e
made from anhydrous hydrazine33 and alkyl halides in a manner similar
to the alkylation of amines.' o n the other hand, alkylation with the
lower halides leads chiefly to di-, tri-, and tetra-substituted hydrazines.'
Ethylhydrazine h a s been obtained by alkylation of hydrazine with ethyl
sulfate (32%).' Methylhydrazine is synthesized by a special variation of
this method (547QO9
If activated by niuo groups, aryl halogens are easily replaced by the
hydrazino group, a s illusuated by the synthesis of 2,4-diniuophenylhydrazine (85%).' Other nitrophenylhydrarines may be obtained by the
action of hydrazine or methylhydra~ine.~
Alkali metal phenylhydrazines, ArN(Na)NH,, which are prepared by
the direct reaction of primary hydrazines with alkali amide in liquid
IH
il'
734
Ch. 26
HYDRAZINES
ammonia are readily alkylated by alkyl halides to furnish N,N-alkylaqdhydrazines, Ar(R)NN& (73-94%).'
sym-Hydrazines, RNHNHR, are prepared by the alkylation of dibenzoylhydrazine (GH,CONHNHCOC&) followed by hydrolytic treatment, a s
shown by the synthesis of sym-dimethylhydrazine (73% over-all).' T h i s
procedure may b e applied to dibenzoylalkylhydrazines which upon alkylation and hydrolysis yield sym-hydrazines substituted with different groups,
e.g., sym-methylisopropylhydrazine.'O
T h e interaction of hydrazine hydrate and ethyl chlorocarbonate in
methanol solution yields methyl hydrazinecarboxylate, &NNHCO,CH,
(49%)."
4 7 2 Interaction of Amines and Hydroxy lamine-0-Sulfclnic Acid
RNH,
+ NH,O.SO,OH
RNHNH,
METHODS 475-478
475. Reduction of Azo Compounds
Aromatic sym-&substituted hydrazines are obtained by reduction of
azo compounds, which in turn are intermediates in properly controlled
reductions of nitro compounds. The over-all reduction can b e accomplished with zinc dust and alkali or electrolytically. For example,
hydnmbenzene, the simplest member, is made by both procedure^.^^*'^
Chemical reduction is carried out on o-nitrobromobenzene t o form 2,Ydibromohydrazobenzene (57%), the halo groups remaining intact." Many
examples of the electrolytic procedure have been cited; the yields vary
from 50% to 95%."' 0
a limited extent, a magnesium-magnesium iodide
system h a s been employed a s a reducting agent for the a ~ o b e n z e n e s . ' ~
476. Action of Grignard Reagents o n Diazomethanez9
Monoalkylhydrazines (C, to C,) are readily prepared by heating amines
with hydroxylamine-0-sulfonic acid in the presence of alkali (31-a%).'
T h e products are isolated a s the oxalate salts.
-
477. Reductive Hydrazination of Carbonyl Compounds 'O
473. Reduction of Diazonium Compounds
NalS 0,
A~N~CI-
ArNHNH, HCI
T h e reduction of diazonium s a l t s by sodium sulfite forms monosubs u t u t e d arylhydrazines. An improved procedure for the synthesis of
phenylhydrazine in 84% yield is typical." Arylhydrazine s a l t s substituted in the nucleus with halo,14 ether," c a r b o ~ y l , ' ~ *or
' ~n i t r ~ " ~ "
groups have been prepared T h e free b a s e s are liberated from the s a l t s
by the action of aqueous sodium hydroxide or sodium acetate.
474 Reduction of Nitrosoamines
R , ~ H(HONO)+ R$JNO
Zn
R,NNH,
CH,COOH
unsym-Disubstituted hydrazines, R&NH,, are prepared by the zincacetic acid reduction of either aliphatic or aromatic nitrosoamines. In
this manner, unsym-dimethylhydrazine is synthesized in 73% yield from
nitrosodimethylamine.'O Similarly, a-methyl-a-phenylhydrazineis prepared (56%)." Preparations of the nitrosoamines from the corresponding
secondary amines are a l s o described.
Ethylhydrazine is made from nitrosodiethylurea, C,H,N(NO)CONHGH,,
by the usual s t e p s of reduction and h y d r o l y s i ~ . ~ ~
R =iaopmpyl (80%)
478. Addition of Grignard Reagents t o Dialkylalkylidenhydrazones"*"
R
= ethyl
(227. over-all)
I
C1
Cl
C,
Compound
Methylhydrazine (as
sul fate)
Ethylhydrazine
Ethylhydratine (as
oxalate)
symDimethylhydrazine
(as hydrochloride)
unsymDimethylhydrazine
Methyl hydrazinocarboxylate
rrPropylhydrazine (as
oxalate)
Isopropylhy drazine
Isopropylhydrazine (as
oralate)
C4 rrhtylhydrazine (as
oxalate)
symMethylisopropy1hydrazine
~,~-~imeth~l-~'ethylhydrazine
CS n-Amylhydrazine (as
oxalate)
symMethy1-n-butylhydraan e
C6
n-Hexylhydrazine
symDii sopmpylhydrazine
Tdethylhydrazine
Phenylhydrazhe
pFluoropheaylhydrazine
cr Nitrophenylhy drdzine
PNitmpheaylhydrazine
2,CDinimphaylhydrazine
Method
N.N-Ethylphcnylhydrarine
2-Phenoryphenylhydrazine
Hydrazobenzene
2,~'-Dibromohydrazobenzene
chap1eflef. B.p./m.,
n
b. (Kp.),
Dedr.
cn
Compound
471
54
269
(142)
cl,
471
472
32
42
26*
26'
99.5/709, l lOHCl
(171)
cj4 ~ e t r a ~ h a y l h y d r a z i n e
471
78
26'
( 167)
474
471
73
49
26m
26"
65/765, 82HCl
108/12, (63), 160HC1
472
52
26'
(175)
477
472
90
44
26*
26'
107/750, 114HC1
(172)
472
45
26'
(165)
471
50
26''
79/37
478
65
26"
77/720, 93Pi
472
31
26'
(164
476
53
26
471
477
26
100
26'
26*
81/14
1241750, 1.4125'4
478
473
473
473
473
471
474
22'
84
74
64
66
85
56
26*'
26U
2614
26"
2617
264
26=
39/37
13W18, (23)
129/21, (39)
(90)*, 140Ac*
(157), 120Pi*
(193
109/13
84
76
2616
2619
(247), 190HCI
253HC1
88
45
85
57
267
26Is
26=
26"
120-7/25, 147HC1
(1 54)
(124)
(98)
C 7 a-Methyl-a-phgylh ydrazine
crCarboryphenylhydratine
473
PCarbox~phenylh~drazine 473
Cm
C,,
TABLE 94 (cvntimcod)
':id
471
473
475
475
"
737
T A B L E 94. HYDRAZINES
TABLE 94. HYDRAZINES
cn
Ch. 26
HYDRAZINES
736
ll5HCl
4,4'-=hydradnodiphenylmethane
Method
(%)
C haptexef. ~.p./mm., ntD.
473
35
z6"
(141)
....
70
26"
(144
gor erplanations and symbols see PP. xi-&
WPA Deriv.
HYDRAZLNES
Ch. 26
REFERENCES FOR CHAPTER 26
'Gever and Hayes, l . 0%. Chem. 14, 813 (1949).
'Westphal, Ber., 74, 759 (1941).
'Brown and Kearley, 1. Am Chem. Soc., 72, 2762 (1950).
4Allen, Org. Syntheses, Coll. Vol. 11, 228 (1943).
'Vis, Rec. trav. cbim.. 58, 387 (1939).
6Koenigs and Loesch, 1. prakt. C h a . 143, 59 (1935).
'Audrieth, Weisigcr, and Carter, I. Org. Chem., 6, 417 (1941).
"Haa, Org. Syntbeses. Coll. Vol. 11, 208 (1943).
'Has, .Org. Syntheses. Coll. Vol. II, 395 (1943).
"~amsperger, 1. Am Cbem Soc.. 51, 918 (1929).
"Diels and Fritzsche, Ber., 44, 3022 (1911).
"Coleman, Org. Syntheses, Coll. Vol. I, 442 (1941).
"Parkes and Morley, I. Chem Soc.. 315 (1936).
14Schiemamand Winkelm"uller, Ber.. 66,729 (1933).
UTarbell et al., I. Am Chem Soc., 70, 1381 (1948).
'6Pfannstiel and Janecke, Ber., 75, 1096 (1942).
"Davies, I. Chem Soc.. 715 (1922).
'"Brady and Repolds, 1. Chem. Soc., 196 (1928).
"Veibel and Hauge, Bull. SOC. chim. France, (5) 5, 1506 (1938).
' O ~ a a , Org. Syntbeses. Coll. Vol. 11, 211 (1943).
"Hartman and Roll, Org. Syntheses, Coll. Vol. 11, 418 (1943).
"Weygand, Organic Preparations, Interscience Publishers, New York, 1945,
p. 241.
"Ganermann and Wieland, Laboratory Methods of Organic Chemistry, The
Macmillan Co., New York, 1938, p. 183; cf. ref. 24.
14McKeeand Gerapostolou, Tmns. Electrochem. Soc., 68, 329 (1935).
%nyder, Weaver, and Marshall, I. Am Chem. Soc., 71, 289 (1949).
"Swann, Trans. Electrocbem Soc., 69, 307 (1936); 77,479 (1940); Swann in
Technique of Organic Chemistry, Vol. 11, Interscience Publishers, New York,
1948, P. 143.
"Bachmam, 1. Am Chem Soc.. 53, 1524 (1931).
'"See ref. 23, p. 355.
a9Colemanet al., I. Org. Chem. 3, 99 (1938).
'O~ochte,Noyes, and Bailey, I. Am Cbem. Soc.. 44, 2556 (1922).
" ~ l a g e s et al., Ann. 547, 1, 28 (1941).
"Westphal and Eucken, Be?., 76, 1137 (1943).
"Smith and Howard, Org. Syntheses, 24, 53 (1944); cf. Barber and Wragg,
I. Chem Soc.. 1458 (1948).
Oximes and Nitroso Compounds
CONTENTS
PAGE
METHOD
739
479. Oximination of Carbonyl Compounds ..........................................................
480. Niuosation of Active Methylene Compounds ............................................ 740
740
481. Partial Reduction of Nitro Compounds ....................................................
741
482. Hydroxylamination of Dihydropyridines ......................................................
741
483. Niuosation of Secondary Amines .............................................................
742
484. Niuosation of an Aromatic Nucleus ..........................................................
742
485. Oxidation of Hy&oxylamines and Amines ...............................................
Table 95. Oximes (Isoniuoso Compounds) ........................................................
Table 9 6 Niuoso Compounds .................................................................... .. . .
743
744
......................................................................................... :............
745
References
479. Oxirnination of Carbonyl Compounds
R,CO
+ H,NOHoHCl + NaOH 4 R,C=NOH + H,O + NaCl
Oximes are commonly prepared by the interaction of ketones with hydroxylamioe hydrochloride (or sulfate) in the presence of an inorganic base.
T h e reaction is reversible, but t h e s t a t e of equilibrium highly favors the
desired products. Preparations of large quantities for synthetic work are
illustrated for methyl ethyl ketoxime,' cyclohexanone oxime,'p3 hepta l d o ~ i m e ,and
~ benzophenone ~ x i m e t,h~e procedures varying somewhat
with the oature of the carbonyl compound. In some instances, a readily
available and cheap reagent like sodium hydroxylamine disulfonate,
HON(SO,Na),, is first prepared from sodium nitrite and sodium bisulfite
and, without isolation, treated with the carbonyl compound,'*617*"
Hydroxylamine-0-sulfonic acid, H,NOSO,H, is still another reagent and,
l i k e sodium hydroxylamine disulfonate, is u s e d in the absence of a base.
T h e preparation of hydroxylamine hydrochloride is described.'
T h e oximes of ketones with large hydrocarbon radicals like t h e acetylphenanthrenes are readily prepared by the action of hydroxylamine hydrochloride in the presence of pyridine."
Special studies have been made
for the synthesis of 1,2-cyclohexanedione d i ~ x i m e 'a~s well a s the next
higher homolog." Dimethylglyoxime, CH3C(=NOH)C(=NOH)CH3, is
740
OXIMES AND NITROSO COMPOUNDS
prepared by the action of sodium hydroxylamine monosulfonate on biacetyl
monoxime."
480. Nitrosation of Active Methylene Compounds
RCOCH,R
+ R'ONO
2RCOC(=NOH)R
+ R'OH
Compounds having active methylene groups react with nitrous acid to
form oximino derivatives. The attack on the a-methylene group of ketones
i s illustiated by the action of ethyl nitrite on methyl ethyl ketone, and
by t h e action of methyl nitrite on propiophenone, to form biacetyl monoxime
(60%)'' and isonitrosopropiophenone (68%),16 respectively. Methyl and
ethyl nitrites are p a s s e d in gaseous form into the ketones in the presence
of hydrochloric acid. In other preparations, ~ b u t y l ,amyl, or octyl nitrite
in liquid form is empl~yed."~''*'~
Similarly, the a-methylene group of acetoacetic ester is oximinated
by the action of sodium nitrite in glacial acetic acid (63%).19 Nitrosaacetoacetic," and benzoylacetic2' e s t e r s
tion of alkylated malonic, "*"
with subsequent cleavage affords an excellent s y n t h e s i s for a-oximino
esters, RC(-NOH)CO,GHS.
A survey of several possible procedures
for t h i s conversion h a s been made." If a P-keto a c i d is nitrosated, then
the carboxyl group is l o s t and an a-oximino ketone is formed, viz.,
CH,COCHRCOIH
(HONO)
CH,COC(=NOH)R
+ CO,
The conversion of o- and p-nitroethylbenzenes with t-butyl nitrite and
sodium t-butoxide into the corresponding nitroacetophenone oximes is
accomplished in 67-74% yields."
481. Partial Reduction of Nitro Compounds
Various procedures have been developed for the production of oximes
from nitroparaffins. Direct reduction with zinc dust and a c e t i c acid h a s
been proposed, but the yields are poor because of the simultaneous formation of a m i n e ~ . ' ~A synthesis for cyclohexanone oxime h a s been demonstrated which involves the formation and selective hydrogenation of 1chloro-I-nitrocyclohexane. T h e halogenated intermediate is prepared in
quantitative yield by chlorination of the sodium s a l t of aci-nitrocyclohexane, and subsequent hydrogenation is performed in an 80% yield over
palladium-on-~harcoal,~'
Still another scheme is concerned with the zinc-acetic acid reduction
of a n aliphatic nitro olefin, which i s readily prepared by the condensation of an aldehyde with the nitroparaffin (method 37)."
74 1
METHODS 481-483
Ch. 27
l
a-Nitrostilbene, C6H5CH=C(N0,)C6H5, is selectively hydrogenated over
a palladium catalyst t o desoxybenzoin oxime in an almost quantitative
yield.a9
4 8 2 Hydroxylamination of Dihydropyridines3'
H
(90% over-all)
483. Nitrosation of Secondary Amines
R,NH HCI
(HONO)
+ R,NNO
Aliphatic and aromatic amines react with nitrous acid t o form N-nitroso
derivatives. For example, dimethylamine hydrochloride on treatment with
sodium nitrite and hydrochloric acid is converted t o nitrosodimethylamine i n 90% yieldbS9 In like manner, N-nitrosomethylaniline i s synthesized from N-methylaniline in 93% yield.40 The ready formation of t h e s e
derivatives and the e a s y reconversion t o t h e amine by reduction affords
an advantageous procedure for separating secondary amines from primary
and tertiary amines, a s shown in t h e s y n t h e s i s of N-ethyl-m-toluidine and
other N-alkyl derivatives by t h e alkylation of m-t~luidine.~'
Certain N-nitroso derivatives are important intermediates in the synthesis of diazomethane and homologs. One synthesis involves t h e nitrosation of a P-alkylaminoisobutyl methyl ketone; the corresponding Nnitrosoamine is readily decomposed to the diazoalkane and mesityl oxide
by treatment with sodium i s o p r ~ p o x i d e . ~ '
(CH,),CC&COCH,
I
(HONO)
* (CH,),CCH,COCH,
I
-
NaOR
CH,N,
+
Other intermediates for the synthesis of diazomethane are nitrosomethylurea, CH,N(NO)CONH,,'~ and nitrosomethylurethane, CH,N(NO)CO,C,H,.'~
Certain a-anilino a c i d s like phenylglycine and a-anilinopropionic acid
have been converted t o their N-nitroso derivatives4'
744
Ch. 27
OXIMES AND NITROSO COMPOUNDS
TABLE 96. NITRaSO COMPOUNDS
C,#
Compound
Melbd
(X)
Chapterref. B.p./mm.,
nf,, MP.)
GNiuoso Gmpounds
l
C,
Nitrosobezae
pfinitmsobezae
~Chloronitmsobezene
~Bromonimsobazee
pNimsopheno1
485
484
485
485
484
53
40'
40
35
80
27'
27''
27"
2747
27=
C
o-Nitrosotoluene
CO pNitmsodimethylaniline
C, p-Nitcosodibhylmiline
485
20
89
95
2747
27"
27"
,
484
484
(67)
(180)
(56)
(97)
(1254
(72.5)
N-Nitrow, Compounds
C,
C,
C,
Nimsodimethylamine
Niuosomethylurea
483
483
90
72
27'9
27U
150/755
N-Nitroso-p-methylamino
isobutyl methyl ketone
N-Nieosomethylmiline
N-Nitrosopheylglycine
483
80'
27"
10Yl.5
483
483
93
90
27"
27U
137/13
(403d)
For explanations md symbols see pp. xi-xii.
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